JP2014521625A - Bicyclic pyrimidone compounds - Google Patents

Abstract

The present invention relates to novel compounds that inhibit Lp-PLA ₂ activity, processes for making them, compositions containing them, and activity of Lp-PLA ₂ exemplifying atherosclerosis, Alzheimer's disease Relates to their use in the treatment of diseases related to the disease.

Description

Background of the Invention

Related Application This application claims the priority of PCT International Patent Application No. PCT / CN2011 / 077772 filed on July 27, 2011 at the National Intellectual Property Office of the People's Republic of China. The entire contents of which are incorporated herein by reference.

TECHNICAL FIELD The present invention relates to novel [6,6] bicyclic pyrimidone compounds, processes for making them, intermediates useful for making them, pharmaceutical compositions containing them, and Lp -Relating to their use in therapy for the treatment of diseases or conditions mediated by PLA ₂ ;

BACKGROUND ART Lipoprotein-related phospholipase A ₂ (Lp-PLA ₂ ), previously known as platelet activating factor acetylhydrolase (PAF-AH), is a phospholipase A2 enzyme involved in the hydrolysis of lipoprotein lipids or phospholipids. is there. Lp-PLA ₂ migrates with low density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules derived from the oxidation of LDL (see, eg, Zalewski A, et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923-31 (2005)). Lp-PLA ₂ hydrolyzes the sn-2 ester of oxidized phosphatidylcholine to give a lipid mediator, lysophosphatidylcholine (lysoPC), and oxidized non-ester fatty acid (NEFA). LysoPC and NEFA have been observed to induce inflammatory responses (see, eg, Zalewski A, et al. (2005)).

Numerous Lp-PLA ₂ inhibitors and / or their use have been reported previously (eg, patent application publication numbers WO 96/13484, WO 96/19451, WO 97/02242, WO 97/12963, WO 97/21675, WO 97 / 21676, WO97 / 41098, WO97 / 41099, WO99 / 24420, WO00 / 10980, WO00 / 66566, WO00 / 66567, WO00 / 68208, WO01 / 60805, WO02 / 30904, WO02 / 30911, WO03 / 015786, WO03 / 016287, WO03 / 041712, WO03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 87088, WO08 / 048867 US 2008/0103156, US 2008/0090851, US 2008/0090852, and WO 08/048866). Disclosed uses include diseases involving or associated with endothelial dysfunction, diseases involving lipid oxidation in conjunction with Lp-PLA ₂ activity (eg, with formation of lysophosphatidylcholine and oxidized free fatty acids), and activity Treatment of diseases involving activated monocytes, macrophages, or lymphocytes, or with increased involvement of monocytes, macrophages, or lymphocytes. Examples of diseases or conditions include atherosclerosis (eg, peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina, ischemia and reperfusion, joints Examples include inflammatory conditions of the brain such as rheumatism, stroke, Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, acute and chronic inflammation, and psoriasis.

Lp-PLA ₂ inhibitors and / or uses thereof are also described, for example, in PCT Publication No. WO05 / 003118 (and its Canadian Family Patent No. CA2530816 A1), WO06 / 063811, WO06 / 063813 and WO2008 / 141176, JP200218847, and US Patents. Application publication numbers US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1 are also reported.

Other researchers have studied the effects associated with Lp-PLA ₂ and its inhibitors. For example, research data indicate that LysoPC promotes the development of atherosclerotic plaque, which can ultimately lead to the formation of necrotic cores (eg, Wilensky et al., Current Opinion in Lipidology , 20, 415-420 (2009)). In addition, the effect of Lp-PLA ₂ inhibitors on atherosclerotic plaque composition was demonstrated in a diabetic and hypercholesterolemic porcine model of rapidly progressive coronary atherosclerosis (eg, Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)). The results of these studies provide further evidence that Lp-PLA ₂ inhibitors can be used to treat atherosclerosis.

From further study, high Lp-PLA ₂ activity was found to be associated with higher risk of dementia, including Alzheimer's disease (AD) (e.g., Van Oijen, et al. Annals of Neurology, 59,139 (2006) See). Higher levels of oxidized LDL have also been observed in AD patients (eg, Kassner et al. Current Alzheimer Research, 5, 358-366 (2008), Dildar, et al., Alzheimer Dis Assoc Disord, 24, April-June (2010), Sinem, et al. Current Alzheimer Research, 7, 463-469 (2010)). Furthermore, study data indicate that neuroinflammation exists in AD patients and that multiple cytotoxic inflammatory cytokines are upregulated in AD patients (eg, Colangelo, et al. , Journal of Neuroscience Research, 70, 462-473 (2002), Wyss-Coray, Nature Medicine, 12, Sept. (2006)). Studies have shown that the function of LysoPC is a pro-inflammatory factor that triggers the release of multiple cytotoxic inflammatory cytokines (Shi, et al. Atherosclerosis, 191, 54-62 (2007) reference). Therefore, this recent study also suggests that it is possible to treat AD by using an inhibitor of Lp-PLA ₂ to inhibit Lp-PLA ₂ activity and reduce lysoPC production Evidence is provided.

In addition, treatment of Lp-PLA ₂ inhibitors in a porcine model of diabetes and hypercholesterolemia reduces blood-brain barrier breakdown and brain amyloid beta protein (Aβ) load, which are pathological features of Alzheimer's disease Has been demonstrated (US Patent Application Publication No. 2008/0279846). This application publication describes several uses of Lp-PLA ₂ inhibitors for the treatment of diseases associated with blood-brain barrier breakdown, including, for example, Alzheimer's disease and vascular dementia.

In addition, neuroinflammation, including the release of multiple cytotoxic inflammatory cytokines, is a common feature of all neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc. (See, for example, Perry, Acta Neuropathol, 120, 277-286 (2010)). As discussed above, Lp-PLA ₂ inhibitors are those that can reduce inflammation, eg, reduce multiple cytokine release by inhibiting lysoPC production (eg, Shi, et al. (See Atherosclerosis 191, 54-62 (2007)). Therefore, inhibiting Lp-PLA ₂ has potential as a treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and the like.

In addition to inflammatory effects, LysoPC has been associated with leukocyte activation, induction of apoptosis, and mediation of endothelial dysfunction (see, eg, Wilensky et al., Current Opinion in Lipidology, 20, 415-420 (2009) reference). Thus, by using the Lp-PLA ₂ inhibitor, by reducing the production of lysoPC those which can cause an increase in the continuity and reactive oxygen species in vascular inflammation cycle (ROS) production, tissue damage related to diabetes It is considered possible to treat. In light of the inflammatory role of Lp-PLA ₂ and the link between local inflammatory processes and diabetic retinopathy, Lp-PLA ₂ can be used to treat diabetic eye disease The hypothesis is made.

Glaucoma and age-related macular degeneration (AMD) are retinal neurodegenerative diseases. Studies have suggested that inflammation, including TNF-alpha signaling, may play an important role in the pathogenesis of glaucoma and AMD (eg, Buschini et al., Progress in Neurobiology, 95, 14-25 ( 2011), Tezel, Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28). Thus, considering the function of Lp-PLA ₂ inhibitors that block the release of inflammatory cytokines (see, eg, Shi, et al. Atherosclerosis, 191, 54-62 (2007)), Lp-PLA ₂ inhibitors are It is believed that it may be possible to provide therapeutic applications for both glaucoma and AMD.

Considering the number of pathological responses mediated by Lp-PLA ₂ , attempts have been made to create compounds that inhibit its activity. Although many such compounds have been disclosed in the art, there remains a continuing need for inhibitors of Lp-PLA ₂ that can be used in the treatment of various disease states.

（式中、
Ｒは、ＨまたはＣ_１‐Ｃ_６アルキルであり、
Ｒ’は、Ｈ、ハロ、またはＣ_１‐Ｃ_６アルキルであり、
Ｘは、−Ｏ−、−ＮＨ−、−Ｎ（Ｃ_１‐Ｃ_６アルキル）−、−Ｓ−、または−ＣＨ_２−であり、
ｎは、０、１、２、または３であり、Ｘが−ＣＨ_２−である場合、ｎは、１または２であり、
Ａｒは、フェニルまたはヘテロアリールであり、これらのいずれも、無置換であるか、またはＣＮ、ハロ、ＯＨ、−ＮＨ_２、−ＮＨＲ_１、−ＮＲ_１Ｒ_２、Ｃ_１‐Ｃ_６アルキル、Ｃ_１‐Ｃ_６アルコキシ、およびＣ_１‐Ｃ_６ハロアルキルからなる群より選択される一つ以上の基で置換されており、ならびに、
Ｙは、存在しないか、または−ＯＡｒ’、−ＮＨ−Ａｒ’、−Ｎ（Ｃ_１‐Ｃ_６アルキル）−Ａｒ’、もしくは−（ＣＨ_２）−Ａｒ’であり、
ここで、Ａｒ’は、フェニルまたはヘテロアリールであり、これらのいずれも、無置換であるか、またはＣＮ、ハロ、ＯＨ、−ＮＨ_２、−ＮＨＲ_１、−ＮＲ_１Ｒ_２、Ｃ_１‐Ｃ_６アルキル、Ｃ_１‐Ｃ_６アルコキシ、およびＣ_１‐Ｃ_６ハロアルキルからなる群より選択される一つ以上の基で置換されており、および、
Ｒ_１およびＲ_２の各存在は、独立して、Ｃ_１‐Ｃ_６アルキルである）。 In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(Where
R is H or C ₁ -C ₆ alkyl;
R ′ is H, halo, or C ₁ -C ₆ alkyl;
X is —O—, —NH—, —N (C ₁ -C ₆ alkyl)-, —S—, or —CH ₂ —;
n is 0, 1, 2, or 3, and when X is —CH ₂ —, n is 1 or 2.
Ar is phenyl or heteroaryl, any of which is unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C ₆ alkyl, C Substituted with one or more groups selected from the group consisting of ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Y is absent or is —OAr ′, —NH—Ar ′, —N (C ₁ -C ₆ alkyl) -Ar ′, or — (CH ₂ ) —Ar ′;
Where Ar ′ is phenyl or heteroaryl, any of which are unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C Substituted with one or more groups selected from the group consisting of ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Each occurrence of R ₁ and R ₂ is independently C ₁ -C ₆ alkyl).

  The invention also relates to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipients.

The present invention also relates to a method of treating a disease associated with the activity of Lp-PLA ₂ , which method comprises treating a subject in need thereof with a therapeutically effective amount of an Lp-PLA ₂ inhibitor. Including. Disease, monocytes, macrophages or increased involvement of lymphocytes, the formation of lysophosphatidylcholine and oxidized free fatty acid can be associated lipid oxidation in conjunction with Lp-PLA ₂ activity, or endothelial dysfunction.

The present invention also provides a method of treating a disease by inhibiting Lp-PLA ₂ activity. Representative diseases include, but are not limited to, neurodegenerative diseases (eg, Alzheimer's disease, vascular dementia), atherosclerosis, stroke, metabolic bone disorders (eg, bone marrow abnormalities), dyslipidemia , Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, and hyperparathyroidism, diabetic eye disorders (eg, macular edema, diabetic retinopathy, and posterior uveitis), macular edema, wound healing, joints Rheumatism, chronic obstructive pulmonary disease (COPD), psoriasis, and multiple sclerosis.

  This method comprises administering a safe effective amount of a compound of the invention to a subject in need thereof. The present invention is not intended to be limited to any particular stage of disease (eg, early or advanced).

  The present invention also provides a method of treating Alzheimer's disease. This method comprises administering a safe effective amount of a compound of the invention to a subject in need thereof.

  The present invention also provides a method of treating atherosclerosis. This method comprises administering a safe effective amount of a compound of the invention to a subject in need thereof.

  The present invention also provides a method of reducing the accumulation of beta amyloid (also referred to as “Aβ”) in the brain of a subject. This method comprises administering a safe effective amount of a compound of the invention to a subject in need thereof. In certain embodiments, the beta amyloid is Abeta-42.

  The present invention also provides methods for treating ocular diseases and disorders by administering the compounds of the present invention. In certain embodiments, the invention provides a method of treating macular edema, the method comprising administering to a subject a safe effective amount of a compound of the invention. In certain embodiments, macular edema is associated with diabetic eye disease, exemplified by diabetic retinopathy. In one embodiment, the macular edema is associated with posterior uveitis.

  The present invention also provides the use of a compound of the present invention in the manufacture of a medicament for treating the diseases described herein.

  The present invention also provides a compound of the present invention for use in the treatments described herein.

Detailed description of the invention

  As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", and "the" are Unless expressly indicated to the contrary, it is intended to include a plurality of forms. Also, as used herein, “and / or” means and includes all possible combinations of one or more of the associated listed items. Further, the terms “comprise” and / or “comprising”, as used herein, refer to the described feature, integer, step, operation, element, and / or component. It is understood that the presence is specified but does not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

  Overall, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, biology, and virology described herein are well known and commonly used in the art. It is what. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. . In cases where there are a plurality of definitions for terms used in this specification, the definitions in this section prevail unless stated otherwise.

  Patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. In case of a conflict in terminology, the present specification will prevail.

A. Definitions As used herein, the term “disease” is any change in the state of the body or in some of the organs that alters and / or disrupts the functioning of the function and / or failure. It refers to a change that causes symptoms such as pleasure, dysfunction, tightness, or even death to an affected or contacted person. The disease can also be distemper, ailing, ailment, malady, disability, sickness, illness, complaint, interdisposition, and / or Or it may include an effectation.

  As used herein, the term “neurodegenerative disease” refers to various combinations of central nervous system disorders characterized by a progressive and progressive loss of neural tissue and / or neural tissue function. A neurodegenerative disease is a neurological disorder or class of diseases, wherein a neurological disease is a gradual and progressive loss of neural tissue and / or a change in neurological function, usually gradual Characterized by a decline in neurological function as a result of progressive loss of neural tissue. In certain embodiments, a neurodegenerative disease described herein is a neurodegenerative disease or disorder in which a blood brain barrier abnormality is present, such as the permeable blood brain barrier. Examples of neurodegenerative diseases in which a blood brain barrier defect exists include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, vascular dementia and the like.

  The term “vascular dementia”, also called “multiple cerebral infarction dementia”, refers to a group of syndromes all caused by various mechanisms that lead to vascular lesions in the brain. The main subtypes of vascular dementia are, for example, vascular mild cognitive impairment, multiple cerebral infarction dementia, vascular dementia due to strategic single infarct, (thalamus, anterior cerebral artery) , Parietal lobe, or cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel diseases (eg, vascular dementia due to pit lesions and binswanger disease), and blood vessels It is mixed Alzheimer's disease with sexual dementia.

  The terms “blood brain barrier” or “BBB” are used interchangeably herein and are present in blood vessels extending through brain tissue and are exchanged between blood and brain tissue. Used to imply a tightly controlled and tightly controlled permeability barrier. The components of the blood brain barrier include endothelial cells that form the innermost layer of all blood vessels, tight junctions between adjacent endothelial cells that are the structural correlate of the BBB, the basement membrane of the endothelial cells, and vascular Adjacent astrocyte elongated foot processes covering almost all of the exposed outer surface.

  As used herein, the phrase “metabolic bone disease” refers to various combinations of bone diseases and disorders characterized by a gradual and progressive loss of bone tissue. The metabolic bone disease described herein is a metabolic bone disease in which there is a pathology of reduced bone density and / or reduced bone strength. Such diseases are characterized by histological findings. Representative metabolic bone diseases include, but are not limited to, osteoporosis characterized by reduced minerals and bone matrix, and osteomalacia characterized by reduced minerals but intact bone matrix. Is mentioned.

  The terms “osteopenia” or “osteopenia” are used interchangeably herein and refer to a condition in which calcification and / or bone density is reduced, A descriptive term used to mean any skeletal system in which a decrease is observed. Osteopenia also means a decrease in bone mass due to inadequate osteoid synthesis.

  The term “osteoporosis” refers to a condition in which minerals and / or bone matrix are reduced and / or bone mass is reduced.

“Alkyl” means a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, C ₁ -C ₆ alkyl means an alkyl group having 1 to 6 carbon atoms. In still other embodiments, the alkyl group contains 1 to 2, 3, 4, or 5 carbon atoms. The alkyl group may be substituted with one or more substituents as defined herein. The alkyl group may be linear or branched. In certain embodiments, the branched alkyl group may have 1, 2, or 3 branched chains. In one embodiment, alkyl is unsubstituted. Representative alkyls include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), methylpropyl, butyl (n-butyl, isobutyl, and t-butyl), pentyl (n- Pentyl, isopentyl, and neopentyl), and hexyl.

  “Alkoxy” refers to the group —O-alkyl. In certain embodiments, the alkoxyl group contains 1 to 2, 3, 4, or 5 carbon atoms. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy.

  “Halogen” means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). “Halo” refers to the halogen radicals: fluoro (—F), chloro (—Cl), bromo (—Br), and iodo (—I).

  “Haloalkyl” has one or more halogen atoms selected from F, Cl, Br, or I, which replace any or all carbons of the alkyl group by replacing a hydrogen atom bonded to the carbon atom. Means an alkyl group as defined above which is substituted on an atom; Exemplary haloalkyl groups include, but are not limited to, chloromethyl, bromoethyl, trifluoromethyl, dichloromethyl.

  “Heteroaryl” means an aromatic ring containing from 1 to 4 heteroatoms as member atoms of the ring. Heteroaryl groups containing two or more heteroatoms may contain different heteroatoms. A heteroaryl group may be optionally substituted with one or more substituents as defined herein. A heteroaryl group is a monocyclic ring system having 5, 6, or 7 member atoms. In certain embodiments, the heteroaryl group is a monocyclic ring system having 6 member atoms. In other embodiments, the heteroaryl group has 1 nitrogen atom as a member atom. In one embodiment, heteroaryl is unsubstituted. Examples of heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, and pyrimidinyl.

  “Optionally substituted” means that a group such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, phenyl, or heteroaryl may be unsubstituted or one such group is defined It shows that it may be substituted with the above substituents.

As used herein, “substituted” with respect to a group is selected from the group of substituents in which one or more hydrogen atoms bonded to a member atom (eg, a carbon atom) within the group are selected. It is replaced with a substituent. The term “substituted” means that such substitution is in accordance with the atom to be substituted and the allowed valence of the substituent and that the substitution is stable (ie, rearranged, cyclized, or eliminated). It is to be understood that this includes the implicit provision that the conversion does not occur spontaneously, as well as results in a compound that is sufficiently robust to withstand isolation from the reaction mixture. Where it is stated that a group may contain one or more substituents, one or more constituent atoms within the group may be (optionally) substituted. In addition, a single member atom within a group may be substituted with two or more substituents so long as such substitution is in accordance with the permitted valence of the atom. Exemplary substituents include, but are not limited to, halo, hydroxyl, amino, amide, -SH, cyano, nitro, thioalkyl, carboxylic acid, -NH-C (= NH) -NH 2, alkyl, alkenyl, Alkynyl, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, aryl, heteroaryl, cycloalkyl, thioalkyl, and heterocycloalkyl are further substituted You can. Suitable substituents are defined herein for each substituted or optionally substituted group.

  As used herein, “treating”, “treating”, or “treatment” with respect to a condition is: (1) one or more remissions of the condition, or biological signs of the condition, (2 ) (A) Interference with one or more parts of the biological cascade leading to or causing the disease state, or (b) Interference with one or more biological signs of the disease state, (3) Related to the disease state Means one or more alleviation of one or more symptoms or effects, and / or (4) a delay in the progression of one or more of the pathology or biological signs of the pathology.

  As used herein, a “subject” refers to a mammalian subject (eg, dog, cat, horse, cow, sheep, goat, monkey, etc.), particularly a human subject including both male and female subjects. , Including newborns, infants, children, adolescents, adults, and elderly subjects, including various races and ethnic groups including, but not limited to, whites, blacks, Asians, American Indians, and Hispanics .

  As used herein, “pharmaceutically acceptable salt” means a salt that retains the desired biological activity of the compound of interest and that has the least undesirable toxic effects shown. To do. These pharmaceutically acceptable salts may be made in situ during the final isolation and purification of the compound or the purified compound in its free acid or free base form, respectively, as appropriate. Or may be made by reacting separately with a base or acid.

  As used herein, an “effective amount” is one in which the amount of a compound of the invention causes a biological or medical response in a tissue, system, animal, or human that is sought, for example, by a researcher or physician. It means that. Further, the term “therapeutically effective amount” refers to an improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a disease or disorder compared to a corresponding subject that has not received such an amount. Means any amount that results in a decrease in the rate of progression. The term also includes within its scope an amount that is effective to improve normal physiological function.

（式中、
Ｒは、ＨまたはＣ_１‐Ｃ_６アルキルであり、
Ｒ’は、Ｈ、ハロ、またはＣ_１‐Ｃ_６アルキルであり、
Ｘは、−Ｏ−、−ＮＨ−、−Ｎ（Ｃ_１‐Ｃ_６アルキル）−、−Ｓ−、または−ＣＨ_２−であり、
ｎは、０、１、２、または３であり、Ｘが−ＣＨ_２−である場合、ｎは、１または２であり、
Ａｒは、フェニルまたはヘテロアリールであり、これらのいずれも、無置換であるか、またはＣＮ、ハロ、ＯＨ、−ＮＨ_２、−ＮＨＲ_１、−ＮＲ_１Ｒ_２、Ｃ_１‐Ｃ_６アルキル、Ｃ_１‐Ｃ_６アルコキシ、およびＣ_１‐Ｃ_６ハロアルキルからなる群より選択される一つ以上の基で置換されており、ならびに、
Ｙは、存在しないか、または−Ｏ−Ａｒ’、−ＮＨ−Ａｒ’、−Ｎ（Ｃ_１‐Ｃ_６アルキル）−Ａｒ’、もしくは−（ＣＨ_２）−Ａｒ’であり、
ここで、Ａｒ’は、フェニルまたはヘテロアリールであり、これらのいずれも、無置換であるか、またはＣＮ、ハロ、ＯＨ、−ＮＨ_２、−ＮＨＲ_１、−ＮＲ_１Ｒ_２、Ｃ_１‐Ｃ_６アルキル、Ｃ_１‐Ｃ_６アルコキシ、およびＣ_１‐Ｃ_６ハロアルキルからなる群より選択される一つ以上の基で置換されており、および、
Ｒ_１およびＲ_２の各存在は、独立して、Ｃ_１‐Ｃ_６アルキルである）。 B. Compounds In a first aspect, the present invention provides the following compounds of formula I and pharmaceutically acceptable salts thereof:

(Where
R is H or C ₁ -C ₆ alkyl;
R ′ is H, halo, or C ₁ -C ₆ alkyl;
X is —O—, —NH—, —N (C ₁ -C ₆ alkyl)-, —S—, or —CH ₂ —;
n is 0, 1, 2, or 3, and when X is —CH ₂ —, n is 1 or 2.
Ar is phenyl or heteroaryl, any of which is unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C ₆ alkyl, C Substituted with one or more groups selected from the group consisting of ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Y is absent or —O—Ar ′, —NH—Ar ′, —N (C ₁ -C ₆ alkyl) -Ar ′, or — (CH ₂ ) —Ar ′;
Where Ar ′ is phenyl or heteroaryl, any of which are unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C Substituted with one or more groups selected from the group consisting of ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Each occurrence of R ₁ and R ₂ is independently C ₁ -C ₆ alkyl).

In one embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, CH ₃ , or iso-propyl;
R ′ is H,
X is —O—, —S—, —NH—, or —CH ₂ —;
n is 1 or 2,
Ar is unsubstituted phenyl, or phenyl substituted with one or more groups selected from the group consisting of CN, F, CF ₃ , Cl, OCH ₃ , and CH ₃ , or Ar is any Is pyridinyl or thiophenyl which is unsubstituted or substituted with one or more F;
Y is absent or is —O—Ar ′, wherein Ar ′ is one or more selected from the group consisting of unsubstituted phenyl, or CF ₃ , F, Cl, CN, and CH _3. Or Ar ′ is a pyridinyl or pyrimidinyl which is either unsubstituted or substituted with one or more groups selected from CF ₃ or CH ₃ is there.

In one embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, CH ₃ , or iso-propyl;
R ′ is H,
X is —O— or —CH ₂ —;
n is 1 or 2,
Ar is unsubstituted phenyl or phenyl substituted with one or more groups selected from the group consisting of CN, F, CF ₃ , Cl, and CH ₃ , or Ar is all unsubstituted Or pyridinyl or thiophenyl, which is substituted with one or more F,
Y is absent or is —O—Ar ′, wherein Ar ′ is one or more selected from the group consisting of unsubstituted phenyl, or CF ₃ , F, Cl, CN, and CH _3. Or Ar ′ is a pyridinyl or pyrimidinyl which is either unsubstituted or substituted with one or more groups selected from CF ₃ or CH ₃ is there.

In one embodiment, the invention relates to compounds of formula (I), wherein R is H, CH ₃ , or iso-propyl, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention relates to compounds of formula (I), wherein R is C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt thereof. In still further embodiments, the invention relates to compounds of formula (I), wherein R is CH ₃ , or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention relates to a compound of formula (I), wherein R is iso-propyl, or a pharmaceutically acceptable salt thereof.

  In another embodiment, the invention relates to a compound of formula (I), wherein R 'is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula (I) wherein X is —O—, —S—, —NH—, or —CH ₂ —, and any of the applicable embodiments above. It relates to a compound, or a pharmaceutically acceptable salt thereof. Furthermore, in one embodiment, the present invention also provides a compound of formula (I) wherein X is —O— and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. Also related. In yet a further embodiment, the invention also relates to a compound of formula (I) wherein X is —NH—, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. .

  In other embodiments, the invention relates to compounds of Formula (I), wherein n is 1 or 2, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also relates to a compound of formula (I) wherein n is 1 and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides that Ar is phenyl substituted with unsubstituted phenyl or one or more groups selected from the group consisting of CN, F, CF ₃ , Cl, and CH ₃ , Or a compound of formula (I) and any of the applicable embodiments above, wherein Ar is pyridinyl or thiophenyl, both unsubstituted or substituted with one or more F Or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention also provides the application of Formula (I) and above, wherein Ar is unsubstituted phenyl, or phenyl substituted with one or more groups independently selected from halo or cyano. It also relates to a compound of any possible embodiment, or a pharmaceutically acceptable salt thereof. In still further embodiments, the present invention also provides that Ar is phenyl, which is substituted with one or more groups independently selected from the group consisting of —F and —CN. And the compounds of any applicable embodiments above, or pharmaceutically acceptable salts thereof. In one embodiment, the present invention also provides that Ar is phenyl substituted with one or more groups independently selected from halo, of any applicable formula (I) and above. It also relates to a form of the compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also provides a compound of formula (I), and any of the applicable embodiments above, wherein Ar is phenyl substituted with one or more F, or a pharmaceutically acceptable salt thereof. It also relates to acceptable salts. In a further embodiment, the present invention also provides a compound of formula (I), wherein Ar is disubstituted phenyl by F, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. Also related. In a further embodiment, the present invention also provides a compound of formula (I), wherein Ar is trisubstituted phenyl by F, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. Also related.

In certain embodiments, the present invention relates to the compound of formula (I), and any of the applicable embodiments above, wherein Y is absent or —O—Ar ′ Where Ar ′ is unsubstituted phenyl or phenyl substituted with one or more groups independently selected from the group consisting of CF ₃ , F, Cl, CN, and CH ₃ , or Ar 'Is pyridinyl or pyrimidinyl, both unsubstituted or substituted with one or more groups independently selected from the group consisting of CF ₃ and CH ₃ . In a further embodiment, the invention also provides that Y is —O—Ar ′ and Ar ′ is substituted with one or more groups independently selected from the group consisting of CF ₃ , F, and Cl. It also relates to a compound of formula (I), and any of the applicable embodiments above, which is phenyl, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention is also applicable to formula (I) and above, wherein Y is —O—Ar ′ and Ar ′ is phenyl substituted with one or more CF _3. It also relates to a compound of any embodiment, or a pharmaceutically acceptable salt thereof. In still further embodiments, the present invention also provides compounds of formula (I) wherein Y is —O—Ar ′ and Ar ′ is phenyl substituted with one or more groups independently selected from halo. And the compounds of any applicable embodiments above, or pharmaceutically acceptable salts thereof. In a further embodiment, the invention also provides a compound of formula (Y) wherein Y is —O—Ar ′ and Ar ′ is phenyl disubstituted with a group independently selected from the group consisting of CF ₃ and halo. It also relates to a compound of I) and any of the applicable embodiments described above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also provides that Y is —O—Ar ′ and Ar ′ is phenyl substituted with one or more groups independently selected from the group consisting of halo and CN. It also relates to a compound of formula (I) and of any applicable embodiment above, or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides one or more groups wherein Y is —O—Ar ′ and Ar ′ is independently selected from the group consisting of CF ₃ , F, CH ₃ , and Cl. Or a pharmaceutically acceptable salt thereof, of the formula (I), and any of the applicable embodiments above, which is pyridinyl substituted with In one embodiment, the present invention also applies to those of formula (I), wherein Y is —O—Ar ′ and Ar ′ is pyridinyl substituted with one or more CF ₃ and above. It also relates to a compound of any possible embodiment, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides compounds of formula (I) wherein Y is —O—Ar ′ and Ar ′ is pyridinyl substituted with one or more groups independently selected from halo. ) And any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also relates to a compound of formula (I), wherein Y is —O—Ar ′, Ar ′ is unsubstituted pyridinyl, and any applicable embodiment above. Or a pharmaceutically acceptable salt thereof.

  In a further embodiment, the invention also relates to a compound of formula (I) in which Y is absent and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of formula (IA):

（式中、Ｒ、Ｒ’、Ｘ、およびｎは、式（Ｉ）で定義され、Ｒａ、Ｒｂ、Ｒｃ、およびＲｄは、Ｈ、ハロ、ＣＦ_３、およびＣＮからなる群より独立して選択される）。

Wherein R, R ′, X, and n are defined in Formula (I), and Ra, Rb, Rc, and Rd are independently selected from the group consisting of H, halo, CF ₃ , and CN )

In a further embodiment, the invention relates to a compound of formula (IA) or a pharmaceutically acceptable salt thereof,
Where
R is H, CH ₃ , or iso-propyl;
R ′ is H,
X is —O—, —S—, —NH—, or —CH ₂ —;
n is 1 or 2,
Ra, Rb, Rc, and Rd are independently selected from the group consisting of H, halo, CF ₃ , and CN.

In yet a further embodiment, the invention relates to a compound of formula (IA) or a pharmaceutically acceptable salt thereof,
Where
R is CH ₃
R ′ is H,
X is —O—,
n is 1,
Ra, Rb, Rc, and Rd are independently selected from the group consisting of hydrogen, halo, CF ₃ , and CN.

In one embodiment, the invention relates to compounds of formula (IA), wherein R is H or C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention, R is H, CH _3, or iso - compounds of formula (IA) propyl, or to a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention relates to compounds of formula (IA), wherein R is CH ₃ , or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention relates to a compound of formula (IA), wherein R is iso-propyl, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the present invention relates to the compound of formula (IA), wherein R ′ is hydrogen, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a compound of formula (IA), wherein X is —O—, —S—, —NH—, or —CH ₂ —, and any of the applicable embodiments above. It relates to a compound, or a pharmaceutically acceptable salt thereof. Furthermore, the invention also relates to compounds of formula (IA) wherein X is —O—, and any of the applicable embodiments described above, or pharmaceutically acceptable salts thereof.

  In certain embodiments, the present invention relates to the compound of formula (IA), wherein n is 1 or 2, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also relates to a compound of formula (IA) wherein n is 1 and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the invention relates to compounds of formula (IA), wherein Ra and Rd are independently selected from the group consisting of CN, F, and H, and any of the applicable embodiments above About. In a further embodiment, the invention also relates to a compound of formula (IA), wherein Ra and Rd are independently selected from the group consisting of F and H, and any of the applicable embodiments above. .

In other embodiments, the invention relates to compounds of Formula (IA), wherein Rb is selected from the group consisting of CF ₃ , F, H, and Cl, and any of the applicable embodiments above. In a further embodiment, the invention also relates to compounds of formula (IA), wherein Rb is CF ₃ or F, and any of the applicable embodiments above.

  In certain embodiments, the present invention relates to compounds of formula (IA), wherein Rc is selected from the group consisting of F, H, and Cl, and of any applicable embodiments above. In still further embodiments, the present invention also relates to compounds of formula (IA), wherein Rc is H or F, and any of the applicable embodiments above.

  In certain embodiments, the compound of formula (I) has the structure of formula (IB):

（式中、Ｒ、Ｒ’、Ｘ、およびｎは、式（Ｉ）で定義され、Ｒｅ、Ｒｆ、およびＲｇは、Ｈ、ハロ、ＣＮ、およびＣＦ_３からなる群より独立して選択される）。

Wherein R, R ′, X, and n are defined in formula (I), and Re, Rf, and Rg are independently selected from the group consisting of H, halo, CN, and CF ₃ ).

In a further embodiment, the invention provides that R, R ′, and n are defined by formula (I), X is —O—, and Re, Rf, and Rg are H, halo, CN, and Relates to compounds of formula (IB) independently selected from the group consisting of CF ₃ .

In certain embodiments, the present invention relates to the compound of formula (IB), wherein R is C ₁ -C ₃ alkyl, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. . In a further embodiment, the invention also relates to a compound of formula (IB) wherein R is CH ₃ and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention also relates to a compound of formula (IB), wherein R is iso-propyl, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. .

  In another embodiment, the invention also relates to a compound of formula (IB) wherein R 'is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In another embodiment, the invention also relates to a compound of formula (IB) wherein n is 1 and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the invention also provides Formula (IB), wherein Re and Rg are independently selected from the group consisting of F, H, and CN, and any of the applicable embodiments above. It also relates to a compound, or a pharmaceutically acceptable salt thereof.

In other embodiments, the invention also provides a compound of Formula (IB), wherein Rf is selected from the group consisting of CF ₃ , H, and Cl, and any of the applicable embodiments above, or It also relates to pharmaceutically acceptable salts.

  In one embodiment, the compound according to formula (I) or formula (IB) is 8-((3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) Oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-α] pyrimidin-6 (2H) -one,

またはその薬学的に許容可能な塩の構造を有する。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the compound of formula (I) has the structure of formula (IC): or a pharmaceutically acceptable salt thereof:

（式中、
Ｒは、ＣＨ_３またはイソ‐プロピルであり、
ｎは、１または２であり、
Ｒｉは、Ｆ、Ｃｌ、およびＨからなる群より選択され、
Ｒｊは、Ｈ、Ｆ、Ｃｌ、ＣＦ_３、ＣＮ、およびＯＣＨ_３からなる群より選択され、
Ｒｈは、Ｈ、Ｆ、Ｃｌ、ＣＮ、およびＣＦ_３からなる群より選択され、ならびに、
Ｒｋは、Ｈ、Ｆ、およびＣＮからなる群より選択される）。

(Where
R is CH ₃ or iso-propyl;
n is 1 or 2,
Ri is selected from the group consisting of F, Cl, and H;
Rj is selected from the group consisting of H, F, Cl, CF ₃ , CN, and OCH ₃ ;
Rh is selected from the group consisting of H, F, Cl, CN, and CF ₃ , and
Rk is selected from the group consisting of H, F, and CN).

In certain embodiments, the present invention also provides compounds of formula (IC) wherein R is CH ₃ or iso-propyl, n is 1, Rj, Rk, and Rh are F, and Ri is H. Or a pharmaceutically acceptable salt thereof.

  In yet a further embodiment, the invention relates to a compound of formula (IC), wherein R is iso-propyl, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention relates to a compound of formula (IC), wherein R is CH ₃ , or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention also relates to a compound of formula (IC), wherein R is iso-propyl, or a pharmaceutically acceptable salt thereof.

  In another embodiment, the invention relates to a compound of formula (IC), wherein n is 1, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a compound of Formula (IC), wherein Rj is selected from the group consisting of H, F, and CF ₃ , and any of the applicable embodiments above, or a pharmaceutical thereof Relating to acceptable salts. In yet a further embodiment, the invention also relates to a compound of formula (IC), wherein Rj is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also relates to a compound of formula (IC), wherein Rj is F, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also relates to a compound of formula (IC), wherein Rj is CF ₃ , and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the present invention relates to the compound of formula (IC), wherein Rk is H or F, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention also relates to compounds of formula (IC), wherein Rk is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention also relates to compounds of formula (IC), wherein Rk is F, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a compound of Formula (IC), wherein Rh is selected from the group consisting of F, Cl, H, and CF ₃ , and any of the applicable embodiments above, or It relates to a pharmaceutically acceptable salt. In a further embodiment, the invention also relates to a compound of formula (IC), wherein Rh is F or H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention also relates to a compound of formula (IC), wherein Rh is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the invention provides a compound of Formula (IC), wherein Ri is selected from the group consisting of F, Cl, and H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof Relates to acceptable salts. In a further embodiment, the invention also relates to a compound of formula (IC), wherein Ri is F or H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention also relates to a compound of formula (IC), wherein Ri is H, and any of the applicable embodiments above, or a pharmaceutically acceptable salt thereof.

  In one embodiment, the compound according to formula (I) or formula (IC) has the following structure or a pharmaceutically acceptable salt thereof:

  In one embodiment, the compound according to formula (I) or formula (IC) has the following structure or a pharmaceutically acceptable salt thereof:

  In one embodiment, the compound according to formula (I) or formula (IC) has the following structure or a pharmaceutically acceptable salt thereof:

  A compound of formula (I), formula (IA), formula (IB), formula (IC), or a pharmaceutically acceptable salt thereof may exist in the form of a stereoisomer (eg, one or more Contains asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also contemplates individual isomers of compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof, as one or more asymmetric centers. Also included as a mixture with the inverted isomers. Similarly, a compound of formula (I), formula (IA), formula (IB), formula (IC), or a pharmaceutically acceptable salt thereof is in the form of a tautomer other than that shown in the formula It is understood that these may also exist within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the specific groups defined above. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. Also within the scope of the present invention are the individual isomers of the compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof, and completely Or any mixture thereof that is partially equilibrated. The present invention also includes individual isomers of compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof, and one or more asymmetric centers. Also included are mixtures with isomers of which is inverted. It is to be understood that the present invention includes all combinations and subsets of the specific groups defined above. Different isomer forms may be separated or resolved from one another by conventional methods, or any isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

  The invention also includes various deuterated forms of the compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof. Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom. The person skilled in the art knows how to synthesize deuterated forms of compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof. Commercially available deuterated starting materials are used to make deuterated forms of compounds of formula (I), formula (IA), formula (IB), formula (IC), or pharmaceutically acceptable salts thereof. Or they may be synthesized using conventional techniques utilizing deuterated reagents (eg, lithium aluminum deuteride).

  In addition to the free base forms of the compounds described herein, salt forms of the compounds are also within the scope of the invention. Pharmaceutically acceptable salts may be made in situ during the final isolation and purification of the compound, or the purified compound in its free acid or free base form can be converted to the appropriate base, respectively. Alternatively, it may be prepared by reacting separately with an acid. For reviews on suitable pharmaceutical salts, see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; PL Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al, See Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453-497.

  In certain embodiments, the compounds of the invention may contain an acidic functional group that is acidic enough to form a salt. Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; pharmaceuticals such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc. And metal carbonates and hydrogen carbonates of pharmaceutically acceptable; aliphatic amines such as methylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine, aromatic amines, aliphatic diamines, and hydroxy Examples include pharmaceutically acceptable organic primary, secondary, and tertiary amines, including alkylamines.

  In certain embodiments, the compounds of the invention may contain a basic group and, therefore, can be treated with a suitable acid to form a pharmaceutically acceptable acid addition salt. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Such salts may be crystalline or amorphous. Typical pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, hydrogen sulfate, sulfamate, phosphate, acetate, hydroxyacetate , Phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate , P-aminosalicylate, glycolate, lactate, heptaneate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate , Dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleic acid , Pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estrate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate Benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), and naphthalene-2-sulfonate. In certain embodiments, pharmaceutically acceptable salts include L-tartrate, ethane disulfonate (edicylate), sulfate, phosphate, p-toluenesulfonate (tosylate), hydrochloride, methanesulfone. Acid salts, citrate salts, fumarate salts, benzenesulfonate salts, maleate salts, hydrobromide salts, L-lactate salts, malonate salts, and S-camphor-10-sulfonate salts. Some of these salts form solvates and some are crystalline.

  The compounds described herein, their pharmaceutically acceptable salts, or any solvate or hydrate thereof may exist as one or more polymorphs. Accordingly, in a further aspect, the invention provides a polymorph of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a solvent of a compound or a pharmaceutically acceptable salt thereof as described herein. A polymorph of a hydrate or hydrate is provided.

C. Compound Synthesis The process to be used to make the compounds described herein depends on the desired compound. Factors such as the choice of a particular substituent and the various possible positions of a particular substituent all play a role in the pathway to be followed in making a particular compound of the invention. These factors are readily recognized by those skilled in the art.

  In general, the compounds of this invention can be made by standard techniques known in the art and by known processes analogous thereto. A general method for making the compounds of the invention is shown below. All starting materials and reagents described in the following general experimental scheme are commercially available.

  One skilled in the art will be able to protect a substituent with an appropriate protecting group that is stable to the reaction conditions if the substituent described herein is incompatible with the synthetic methods described herein. Understood. The protecting group can be removed at an appropriate point in the reaction pathway to provide the desired intermediate or desired compound. Suitable protecting groups and methods for the protection and deprotection of various substituents by using such suitable protecting groups are known to those skilled in the art, examples of which are described in T. Greene and P. Wuts , Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some examples, the substituents may be specifically selected to be reactive under the reaction conditions used. Under such circumstances, the reaction conditions convert the selected substituent to another substituent that is useful as an intermediate compound or that is a desired substituent in the compound of interest.

General experimental scheme 1 provides a representative synthesis for compounds 6 and 7. In Scheme 1, R _x is H or — (C ₁ -C ₆ ) alkyl, R _y is — (CH ₂ ) _n —Ar—Y, X is O or S, R ′ , R, Ar, Y, and n are as defined in formula (I). Step (i) comprises reacting compound 1 with compound 2 using a suitable reagent such as KI in a suitable solvent such as H ₂ O at a suitable temperature such as 120 ° C. using microwave irradiation. Compound 3 can be obtained. Step (ii) is an intramolecular Mitsunobu reaction using a suitable reagent such as diisopropyl azodicarboxylate (DIAD) and Ph ₃ P in a suitable solvent such as THF at a suitable temperature such as room temperature. Good. Step (iii) may be performed by reacting compound 4 with a suitable reagent such as POCl ₃ in a suitable solvent such as POCl ₃ at a suitable temperature such as 90 ° C.

Step (iv), at a suitable temperature such as 0 ° C., in a suitable solvent such as dimethylformamide (DMF), in the presence of a suitable base such as NaH, compound 5 Y-Ar- (CH ₂ ) _N XH to give compound 6 where R, R ′, Ar, Y, and n are as defined in formula (I), where X is O or S It is.

Step (v) comprises compound 5 with R _x R _y NH in the presence of a suitable base such as triethylamine (TEA) in a suitable solvent such as dimethylformamide (DMF) at a suitable temperature of 140 ° C. The reaction can be carried out to give compound 7.

General experimental scheme 2 provides another alternative synthesis for compound 11. In Scheme 2, X is O, and Ar, Y, and n are as defined in Formula (I). Step (i) is performed by reacting compound 8 with Y—Ar— (CH ₂ ) _n XH using a suitable base such as NaH in a suitable solvent such as DMF at a suitable temperature such as room temperature. Compound 9 is obtained. Step (ii) is carried out at a suitable temperature such as 0 ° C. in a suitable solvent such as DMF with a suitable reagent such as 3-bromopropan-1-amine and a suitable base such as DIPEA. Well, compound 10 is obtained. Step (iii) may be performed by hydrolysis of compound 10 with a suitable base such as K ₂ CO ₃ in a suitable solvent such as 1,4-dioxane and water at a suitable temperature such as 50 ° C. Compound 11 is obtained.

General experimental scheme 3 provides a synthesis as a different alternative for compound 11. In Scheme 3, X is O, and Ar, Y, and n are as defined in formula (I). Step (i) comprises reacting compound 8 with 3-bromopropan-1-amine using a suitable base such as Et ₃ N in a suitable solvent such as CH ₃ CN at a suitable temperature such as room temperature. To give compound 12. Step (ii) may be performed at a suitable temperature such as 60 ° C. with a suitable base such as K ₂ CO ₃ in a suitable solvent such as 1,4-dioxane, to give compound 13. . Step (iii) may be performed by reacting compound 13 with (Boc) ₂ O together with a suitable catalyst such as DMAP in a suitable solvent such as THF at a suitable temperature such as room temperature. Is obtained. Step (iv) reacts compound 14 with Y—Ar— (CH ₂ ) _n XH in the presence of a suitable base such as NaH in a suitable solvent such as THF at a suitable temperature such as 0 ° C. Compound 15 is obtained. Step (v) may be performed by reacting compound 15 with a suitable acid, such as HCl, in a suitable solvent, such as 1,4-dioxane, at a suitable temperature, such as room temperature, to obtain compound 11. It is done.

General experimental scheme 4 provides a representative synthesis for compound 20. In scheme 4, R, R ′, n, Ar, and Y are as defined in formula (I). Step (i) may be performed by reacting compound 16 with compound 17 using a suitable reagent such as K ₂ CO ₃ in a suitable solvent such as MeOH at a suitable temperature such as room temperature, Compound 18 is obtained. Step (ii) used a suitable reagent such as Pd ₂ (dba) ₃ , CuI, TEA, and (2-fur) ₃ P in a suitable solvent such as toluene at a suitable temperature such as 50 ° C. It may be a Sonogashira reaction of compound 18 and compound 5. Step (iii) is carried out by hydrogenating compound 19 with a suitable reagent such as Pd / C in a suitable solvent such as MeOH in a suitable solvent such as MeOH in a H ₂ atmosphere such as 1 bar. Compound 20 is obtained.

  All temperatures are reported in degrees Celsius. All other abbreviations are as described in ACS Style Guide (American Chemical Society, Washington, DC, 1986).

LCMS conditions:
1) Acidic conditions:
Mobile phase: 0.05% TFA-containing water / 0.05% acetonitrile Column: Agilent SB-C18 4.6 × 30 mm-1.8 micron Detection: MS and photodiode array detector (PDA)
2) Basic conditions:
Mobile phase: 10 mmol NH ₄ HCO ₃ -containing water / acetonitrile Column: XBridge ™ C18 4.6 × 50 mm-3.5 micron Detection: MS and photodiode array detector (PDA)

Mass directed autoprep purification (MDAP) conditions:
1) Acidic conditions:
Apparatus: Waters apparatus Column: Sunfire Prep C18 column (5um, 19x50mm)
Mobile phase: 0.05% TFA-containing water / acetonitrile 2) Basic conditions:
Equipment: Waters equipment Column: Xbridge Prep C18 column (5um, 19x50mm)
Mobile phase: 0.04% ammonia-containing water / acetonitrile

Abbreviations and Information Sources The following abbreviations and information sources are used herein below:
ISCO system-Teledyne ISCO (http://www.isco.com/html/seFlashChromatography.html)
r. t / rt / RT-room temperature,
ACN-acetonitrile,
AcCl-acetic acid chloride,
Aq. -Aqueous,
(BOC) ₂ O-di-tert-butyl dicarbonate,
CV-column volume,
DABCO-1,4-diazabicyclo [2.2.2] octane,
DAST-diethylaminosulfur trifluoride,
DBU-1,8-diazabicyclo [5.4.0] undec-7-ene DCM-dichloromethane,
DIAD-Diisopropyl azodiformate,
DIPEA-N, N-diisopropylethylamine,
DMA-N, N-dimethylacetamide,
DMAP-4-dimethylaminopyridine,
DME-1,2-dimethoxyethane,
DMF-dimethylformamide,
DMSO-dimethyl sulfoxide,
EA-ethyl acetate,
EDC-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride,
FC-flash chromatography,
HATU-2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium,
NBS-N-bromosuccinamide,
NIS-N-iodosuccinimide,
NMP-N-methyl-2-pyrrolidone,
TEA-triethylamine,
TFA-trifluoroacetic acid,
THF-tetrahydrofuran,
PE-petroleum ether,
DIBAL-H-diisobutylaluminum hydride,
9-BBN-9-borabicyclo [3.3.1] nonane.

  The following synthetic processes and examples are provided to more specifically illustrate the present invention. These examples are not intended to limit the scope of the invention, but provide guidance to one of ordinary skill in the art for making and using the compounds, compositions, and methods of the invention. While specific embodiments of the present invention are described, it will be appreciated by those skilled in the art that various modifications and changes may be made without departing from the spirit and scope of the invention.

D1: 6-((3-hydroxypropyl) (methyl) amino) pyrimidine-2,4 (1H, 3H) -dione

３‐（メチルアミノ）プロパン‐１‐オール（５８８ｍｇ、６．６ｍｍｏｌ）、６‐クロロピリミジン‐２，４（１Ｈ，３Ｈ）‐ジオン（４４０ｍｇ、３．０ｍｍｏｌ）、ＫＩ（４．９８ｍｇ、０．０３ｍｍｏｌ）、および水（６ｍＬ）を、マイクロ波反応管に投入した。この混合物を、マイクロ波照射（Ｂｉｏｔａｇｅイニシエーター）によって１２０℃に加熱し、１２０℃にて２時間攪拌した。この反応混合物を、質量分析付き自動分取で精製して、６‐（（３‐ヒドロキシプロピル）（メチル）アミノ）ピリミジン‐２，４（１Ｈ，３Ｈ）‐ジオン，トリフルオロ酢酸塩（５３８ｍｇ、１．７１８ｍｍｏｌ、収率５７．３％）を白色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２００［Ｍ＋Ｈ］^＋；０．４６分（保持時間）

3- (Methylamino) propan-1-ol (588 mg, 6.6 mmol), 6-chloropyrimidine-2,4 (1H, 3H) -dione (440 mg, 3.0 mmol), KI (4.98 mg, 0. 03 mmol) and water (6 mL) were added to the microwave reaction tube. The mixture was heated to 120 ° C. by microwave irradiation (Biotage initiator) and stirred at 120 ° C. for 2 hours. The reaction mixture was purified by automated preparative mass spectrometry to give 6-((3-hydroxypropyl) (methyl) amino) pyrimidine-2,4 (1H, 3H) -dione, trifluoroacetate (538 mg, 1.718 mmol, 57.3% yield) was obtained as a white solid.
LC-MS (ESI): m / z 200 [M + H] ⁺ ; 0.46 minutes (retention time)

D2: 1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6,8 (2H, 7H) -dione

Ｐｈ_３Ｐ（８５４ｍｇ、３．２６ｍｍｏｌ）を、ＴＨＦ（１４０ｍＬ）中の６‐（（３‐ヒドロキシプロピル）（メチル）アミノ）ピリミジン‐２，４（１Ｈ，３Ｈ）‐ジオン，トリフルオロ酢酸塩（３４０ｍｇ、１．０８５ｍｍｏｌ）の懸濁液へ室温にて添加し、次に、ＤＩＡＤ（０．６３３ｍＬ、３．２６ｍｍｏｌ）を滴下した。この反応混合物を、室温にて３時間攪拌した。この反応混合物を、真空濃縮し、得られた残渣を、ジエチルエーテルと水とに分配した。水相を分離し、エチルエーテルで再度洗浄し、次に真空濃縮して、１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６，８（２Ｈ，７Ｈ）‐ジオン，トリフルオロ酢酸塩（２７８ｍｇ、０．９４２ｍｍｏｌ、収率８７％）をオフホワイト色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ １８２［Ｍ＋Ｈ］^＋、０．７７分（保持時間）

Ph ₃ P (854 mg, 3.26 mmol) was added to 6-((3-hydroxypropyl) (methyl) amino) pyrimidine-2,4 (1H, 3H) -dione, trifluoroacetate salt in THF (140 mL). To a suspension of 340 mg, 1.085 mmol) at room temperature, then DIAD (0.633 mL, 3.26 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether and water. The aqueous phase was separated, washed again with ethyl ether, then concentrated in vacuo and 1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6,8 (2H, 7H) -Dione, trifluoroacetate (278 mg, 0.942 mmol, 87% yield) was obtained as an off-white solid.
LC-MS (ESI): m / z 182 [M + H] ⁺ , 0.77 minutes (retention time)

D3: 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

ＰＯＣｌ_３（１２ｍＬ、１２９ｍｍｏｌ）中の１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６，８（２Ｈ，７Ｈ）‐ジオン，トリフルオロ酢酸塩（０．２５３ｇ、０．８５７ｍｍｏｌ）の懸濁液を、９０℃にて６時間攪拌した。加熱後、元の懸濁液は、均質な溶液に変化した。この混合物を真空濃縮してＰＯＣｌ_３を除去した。得られた残渣に氷水を添加し、次に、固体ＮａＯＨを滴下してｐＨを約１２に調節した。この溶液を室温にて２時間攪拌した。ＨＣｌ水溶液（１Ｍ）を添加してｐＨを約７に調節した。この溶液を質量分析付き自動分取に掛けて、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン，トリフルオロ酢酸塩（２６０ｍｇ、０．８２９ｍｍｏｌ、収率９７％）を白色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２００［Ｍ＋Ｈ］^＋、０．５２分（保持時間）

1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6,8 (2H, 7H) -dione, trifluoroacetate (0.253 g) in POCl ₃ (12 mL, 129 mmol) , 0.857 mmol) was stirred at 90 ° C. for 6 hours. After heating, the original suspension turned into a homogeneous solution. The mixture was concentrated in vacuo to remove POCl ₃ . Ice water was added to the resulting residue, then solid NaOH was added dropwise to adjust the pH to about 12. The solution was stirred at room temperature for 2 hours. Aqueous HCl (1M) was added to adjust the pH to about 7. This solution was subjected to automated fractionation with mass spectrometry to give 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one, trifluoroacetate (260 mg, 0.829 mmol, 97% yield) was obtained as a white solid.
LC-MS (ESI): m / z 200 [M + H] ⁺ , 0.52 minutes (retention time)

D4: 5-Formyl-2-{[3- (trifluoromethyl) phenyl] oxy} benzonitrile

炭酸カリウム（１．８５ｇ、１３．４１ｍｍｏｌ）を、ＤＭＦ（１０ｍＬ）中の２‐フルオロ‐５‐ホルミル‐ベンゾニトリル（２．０ｇ、１３．４１ｍｍｏｌ）および３‐トリフルオロメチル‐フェノール（１．６３ｍＬ、１３．４１ｍｍｏｌ）の溶液へ添加した。この反応混合物を、マイクロ波照射を用い、６０℃にて２時間攪拌した。得られた混合物をろ過し、次に濃縮した。ＦＣによる精製により、表題の化合物を白色固体として得た（３ｇ、収率７３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９２［Ｍ＋Ｈ］^＋、３．３８分（保持時間）

Potassium carbonate (1.85 g, 13.41 mmol) was added to 2-fluoro-5-formyl-benzonitrile (2.0 g, 13.41 mmol) and 3-trifluoromethyl-phenol (1.63 mL) in DMF (10 mL). , 13.41 mmol). The reaction mixture was stirred at 60 ° C. for 2 hours using microwave irradiation. The resulting mixture was filtered and then concentrated. Purification by FC gave the title compound as a white solid (3 g, 73% yield).
LC-MS (ESI): m / z 292 [M + H] ⁺ , 3.38 minutes (retention time)

D5: 5- (hydroxymethyl) -2-{[3- (trifluoromethyl) phenyl] oxy} benzonitrile

メタノール（３０ｍＬ）中の５‐ホルミル‐２‐｛［３‐（トリフルオロメチル）フェニル］オキシ｝ベンゾニトリル（５ｇ、１７．１７ｍｍｏｌ）の溶液へ、ＮａＢＨ_４（０．３９ｇ、１０．３０ｍｍｏｌ）を０℃にて添加し、次に、室温にて３０分間攪拌した。この反応混合物を、アセトンで反応停止し、濃縮した。残渣をＩＳＣＯ（ＤＣＭ：ＭｅＯＨ＝２０：１）で精製して、表題の化合物を透明オイルとして得た（５．５ｇ、収率９５％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９４［Ｍ＋Ｈ］^＋、３．０９分（保持時間）
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：７．７２（ｓ，１Ｈ），７．５（ｍ，３Ｈ），７．３２（ｓ，１Ｈ），７．２５（ｓ，１Ｈ），６．９２（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），４．７２（ｓ，２Ｈ）

To a solution of 5-formyl-2-{[3- (trifluoromethyl) phenyl] oxy} benzonitrile (5 g, 17.17 mmol) in methanol (30 mL) was added NaBH ₄ (0.39 g, 10.30 mmol). Added at 0 ° C. and then stirred at room temperature for 30 minutes. The reaction mixture was quenched with acetone and concentrated. The residue was purified by ISCO (DCM: MeOH = 20: 1) to give the title compound as a clear oil (5.5 g, 95% yield).
LC-MS (ESI): m / z 294 [M + H] ⁺ , 3.09 minutes (retention time)
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.72 (s, 1H), 7.5 (m, 3H), 7.32 (s, 1H), 7.25 (s, 1H), 6.92 (D, J = 8.8 Hz, 1H), 4.72 (s, 2H)

D6: 2-hydroxy-5-iodobenzonitrile

ＣＨ_３ＣＮ（５００ｍＬ）中の２‐ヒドロキシ‐ベンゾニトリル（４７．６ｇ、０．４００ｍｍｏｌ）の溶液へ、ＣＦ_３ＳＯ_３Ｈ（４０ｍＬ）を０℃にて滴下し、次に０℃にて２０分間攪拌し、次にＮＩＳ（１０８ｇ、０．４８ｍｍｏｌ）を添加した。この反応混合物を、室温にて一晩攪拌し、濃縮し、次にＨ_２Ｏ（３００ｍＬ）で希釈し、ＥＡで抽出した（３００ｍＬ×３）。一つにまとめた有機部分を、無水Ｎａ_２ＳＯ_４上で乾燥し、ろ過し、濃縮した。ＦＣ（ＰＥ／ＥｔＯＡｃ＝５／１）で精製して、表題の化合物を白色固体として得た（８０ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：７．７８（ｓ，１Ｈ），７．７０（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ）

CF ₃ SO ₃ H (40 mL) was added dropwise at 0 ° C. to a solution of 2-hydroxy-benzonitrile (47.6 g, 0.400 mmol) in CH ₃ CN (500 mL), then at 20 ° C. Stir for minutes and then add NIS (108 g, 0.48 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, then diluted with H ₂ O (300 mL) and extracted with EA (300 mL × 3). The combined organic portion was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Purification by FC (PE / EtOAc = 5/1) gave the title compound as a white solid (80 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.78 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H)

D7: 5-iodo-2-((5- (trifluoromethyl) pyridin-2-yl) oxy) benzonitrile

ＤＭＦ（５００ｍＬ）中の２‐ヒドロキシ‐５‐ヨードベンゾニトリル（８０．０ｇ、０．３２８ｍｏｌ）および２‐クロロ‐５‐トリ‐フルオロメチル‐ピリジン（６０．０ｇ、０．３２８ｍｏｌ）の溶液へ、Ｋ_２ＣＯ_３（９１．０ｇ、０．６５６ｍｏｌ）を添加した。この反応混合物を、一晩還流し、ろ過し、濃縮した。ＦＣ（ＰＥ／ＥｔＯＡｃ＝１０／１）で精製して、表題の生成物を白色固体として得た（１２０ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：８．３８（ｓ，１Ｈ），８．０１（ｍ，２Ｈ），７．９５（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），８．０８（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．６８（ｓ，１Ｈ）

To a solution of 2-hydroxy-5-iodobenzonitrile (80.0 g, 0.328 mol) and 2-chloro-5-trifluoromethyl-pyridine (60.0 g, 0.328 mol) in DMF (500 mL) K ₂ CO ₃ (91.0 g, 0.656 mol) was added. The reaction mixture was refluxed overnight, filtered and concentrated. Purification by FC (PE / EtOAc = 10/1) gave the title product as a white solid (120 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.38 (s, 1H), 8.01 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H)

D8: Methyl 3-cyano-4-((5- (trifluoromethyl) pyridin-2-yl) oxy) benzoate

メタノール（１５００ｍＬ）およびＤＭＦ（４００ｍＬ）中の５‐ヨード‐２‐（５‐トリフルオロメチル‐ピリジン‐２‐イルオキシ）‐ベンゾニトリル（１１０ｇ、０．２９ｍｏｌ）の溶液へ、Ｐｄ（ｄｐｐｆ）Ｃｌ_２（２０ｇ）を添加した。この反応混合物を、オートクレーブ（１０Ｌ）中、ＣＯ（１ＭＰａ）下、１００℃にて７２時間攪拌した。メタノールおよびＤＭＦを真空除去した。ＦＣ（ＰＥ：ＥｔＯＡｃ＝２０：１から１０：１）で精製して、表題の化合物を黄色オイルとして得た（４５ｇ、４８％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：８．３９（ｓ，１Ｈ），８．２９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．０１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．４０（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），３．９４（ｓ，３Ｈ）．

To a solution of 5-iodo-2- (5-trifluoromethyl-pyridin-2-yloxy) -benzonitrile (110 g, 0.29 mol) in methanol (1500 mL) and DMF (400 mL), Pd (dppf) Cl ₂ (20 g) was added. The reaction mixture was stirred for 72 hours at 100 ° C. in CO (1 MPa) in an autoclave (10 L). Methanol and DMF were removed in vacuo. Purification by FC (PE: EtOAc = 20: 1 to 10: 1) gave the title compound as a yellow oil (45 g, 48%).
¹ H NMR (400 MHz, CDCl 3) δ: 8.39 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 7 .40 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H).

D9: 5- (hydroxymethyl) -2-((5- (trifluoromethyl) pyridin-2-yl) oxy) benzonitrile

無水ＴＨＦ（２００ｍＬ）中の３‐シアノ‐４‐（５‐トリフルオロメチル‐ピリジン‐２‐イルオキシ）‐安息香酸メチルエステル（２３ｇ、０．０７０ｍｏｌ）の溶液へ、ＬｉＡｌＨ_４（４．０７ｇ、０．１１ｍｍｏｌ）を−７８℃にて少しずつ添加した。この反応混合物を−５５℃までゆっくり加温し、２０分間攪拌し、水（３ｍＬ ０．１６ｍｍｏｌ、ゆっくり添加）で希釈し、ろ過し、濃縮した。ＦＣ（ＰＥ／ＥｔＯＡｃ＝１０／１から５／１）で精製して、表題の生成物を無色オイルとして得た（１２．５ｇ）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ：８．３７（ｓ，１Ｈ），７．９８（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．７２（ｓ，１Ｈ），７．６４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ）

To a solution of 3-cyano-4- (5-trifluoromethyl-pyridin-2-yloxy) -benzoic acid methyl ester (23 g, 0.070 mol) in anhydrous THF (200 mL), LiAlH ₄ (4.07 g, 0 .11 mmol) was added in portions at -78 ° C. The reaction mixture was slowly warmed to −55 ° C., stirred for 20 minutes, diluted with water (3 mL 0.16 mmol, slowly added), filtered and concentrated. Purification by FC (PE / EtOAc = 10/1 to 5/1) gave the title product as a colorless oil (12.5 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.37 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H)

D10: 3,5-Difluoro-4-((6- (trifluoromethyl) -3-pyridinyl) oxy) benzaldehyde

市販の３，４，５‐トリフルオロベンズアルデヒド（１ｇ、６．２５ｍｍｏｌ）、６‐（トリフルオロメチル）‐３‐ピリジノール（１．０１９ｇ、６．２５ｍｍｏｌ）、およびＫ_２ＣＯ_３（１．７２７ｇ、１２．４９ｍｍｏｌ）を、マイクロ波バイアルに投入した。次に、Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（１５ｍＬ）を添加した。マイクロ波バイアルを密封し、Ｂｉｏｔａｇｅイニシエータ中、１００℃にて１時間加熱した。この混合物を、ＥｔＯＡｃで抽出した。有機抽出物を、Ｎａ_２ＳＯ_４上で乾燥し、蒸発させて、１．７８ｇの表題の生成物を得た（９４％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０４［Ｍ＋Ｈ］^＋、３．３１分（保持時間）

Commercial 3,4,5-trifluorobenzaldehyde (1 g, 6.25 mmol), 6- (trifluoromethyl) -3-pyridinol (1.019 g, 6.25 mmol), and K ₂ CO ₃ (1.727 g, 12.49 mmol) was placed in a microwave vial. Next, N, N-dimethylformamide (DMF) (15 mL) was added. The microwave vial was sealed and heated in a Biotage initiator at 100 ° C. for 1 hour. This mixture was extracted with EtOAc. The organic extract was dried over Na ₂ SO ₄ and evaporated to give 1.78 g of the title product (94%).
LC-MS (ESI): m / z 304 [M + H] ⁺ , 3.31 minutes (retention time)

D11: (3,5-difluoro-4-((6- (trifluoromethyl) -3-pyridinyl) oxy) phenyl) methanol

メタノール（１５ｍＬ）中の３，５‐ジフルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）ベンズアルデヒド（１．７８ｇ、５．８７ｍｍｏｌ）の溶液へ、ＮａＢＨ_４（０．２２２ｇ、５．８７ｍｍｏｌ）を添加した。この混合物を、室温にて０．５時間攪拌した。ＮＨ_４Ｃｌ溶液をこの反応混合物へ添加し、この反応混合物をＤＣＭで抽出した。次に、有機相を、Ｎａ_２ＳＯ_４上で乾燥し、蒸発させて、生成物を得た（１．７０２ｇ、９５％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０６［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

To a solution of 3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzaldehyde (1.78 g, 5.87 mmol) in methanol (15 mL) was added NaBH ₄ (0. 222 g, 5.87 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. NH ₄ Cl solution was added to the reaction mixture and the reaction mixture was extracted with DCM. The organic phase was then dried over Na ₂ SO ₄ and evaporated to give the product (1.702 g, 95%).
LC-MS (ESI): m / z 306 [M + H] ⁺ , 3.02 minutes (retention time)

D12: 3-Fluoro-4-((6- (trifluoromethyl) -3-pyridinyl) oxy) benzaldehyde

表題の化合物を、６‐（トリフルオロメチル）３‐ピリジノールおよび３，４‐ジフルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８６［Ｍ＋Ｈ］^＋、３．２０分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 6- (trifluoromethyl) 3-pyridinol and 3,4-difluorobenzaldehyde.
LC-MS (ESI): m / z 286 [M + H] ⁺ , 3.20 minutes (retention time)

D13: (3-Fluoro-4-((6- (trifluoromethyl) -3-pyridinyl) oxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（（６‐（トリフルオロメチル）‐３‐ピリジニル）オキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８８［Ｍ＋Ｈ］^＋、２．８８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4-((6- (trifluoromethyl) -3-pyridinyl) oxy) benzaldehyde.
LC-MS (ESI): m / z 288 [M + H] ⁺ , 2.88 minutes (retention time)

D14: 4- (3,4-Fluorophenoxy) -3-fluoro-benzaldehyde

表題の化合物を、３，４‐ジフルオロフェノールおよび３，４‐ジフルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋Ｈ］^＋、３．３４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorophenol and 3,4-difluorobenzaldehyde.
LC-MS (ESI): m / z 253 [M + H] ⁺ , 3.34 minutes (retention time)

D15: (4- (3,4-Fluorophenoxy) -3-fluorophenyl) methanol

表題の化合物を、４‐（３，４‐フルオロフェノキシ）‐３‐フルオロ‐ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３７［Ｍ−１７］^＋、２．９９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3,4-fluorophenoxy) -3-fluoro-benzaldehyde.
LC-MS (ESI): m / z 237 [M-17] ⁺ , 2.99 minutes (retention time)

D16: 4- (4-Chloro-3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、４‐クロロ‐３‐トリフルオロメチル‐フェノールおよび４‐フルオロ‐ベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０１［Ｍ＋１］^＋、３．７９分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-chloro-3-trifluoromethyl-phenol and 4-fluoro-benzaldehyde.
LC-MS (ESI): m / z 301 [M + 1] ⁺ , 3.79 minutes (retention time)

D17: (4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ−１７］^＋、３．４８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (4-chloro-3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 285 [M-17] ⁺ , 3.48 minutes (retention time)

D18: 4- (3,4-Dichlorophenoxy) benzaldehyde

表題の化合物を、３，４‐ジクロロフェノールおよび４‐フルオロ‐ベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６８［Ｍ＋１］^＋、３．７９分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-dichlorophenol and 4-fluoro-benzaldehyde.
LC-MS (ESI): m / z 268 [M + 1] ⁺ , 3.79 minutes (retention time)

D19: (4- (3,4-Dichlorophenoxy) phenyl) methanol

表題の化合物を、４‐（３，４‐ジクロロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５１［Ｍ−１７］^＋、３．４２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3,4-dichlorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 251 [M-17] ⁺ , 3.42 minutes (retention time)

D20: (E) -1-chloro-4- (4- (2-nitrovinyl) phenoxy) -2- (trifluoromethyl) benzene

ＨＯＡｃ（４０ｍＬ）中の４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒド（１３ｇ、４３．２ｍｍｏｌ）および酢酸アンモニウム（１．６７ｇ、２１．６２ｍｍｏｌ）の溶液へ、ニトロメタン（６．９９ｍＬ、１３０ｍｍｏｌ）を添加した。この反応混合物を、１２０℃にて５時間攪拌し、濃縮した。残渣をＤＣＭ（１５０ｍＬ）に溶解し、飽和ＮａＨＣＯ_３水溶液（１００ｍＬ×２）、鹹水で洗浄し、次に、無水Ｎａ_２ＳＯ_４上で乾燥し、濃縮して、表題の化合物を褐色固体として得た（１４．３ｇ、収率６３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ＭＳシグナルなし、１．９７分（保持時間）

To a solution of 4- (4-chloro-3- (trifluoromethyl) phenoxy) benzaldehyde (13 g, 43.2 mmol) and ammonium acetate (1.67 g, 21.62 mmol) in HOAc (40 mL), nitromethane (6. 99 mL, 130 mmol) was added. The reaction mixture was stirred at 120 ° C. for 5 hours and concentrated. The residue was dissolved in DCM (150 mL), washed with saturated aqueous NaHCO ₃ (100 mL × 2), brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a brown solid. (14.3 g, 63% yield).
LC-MS (ESI): no MS signal, 1.97 minutes (retention time)

D21: 1-chloro-4- (4- (2-nitroethyl) phenoxy) -2- (trifluoromethyl) benzene

ｉ‐ＰｒＯＨ（１５５ｍＬ）およびＣＨＣｌ_３（４６５ｍＬ）中の（Ｅ）‐１‐クロロ‐４‐（４‐（２‐ニトロビニル）フェノキシ）‐２‐（トリフルオロメチル）ベンゼン（１３ｇ、４３．２ｍｍｏｌ）およびシリカゲル（１２０ｇ、１００‐２００メッシュ）の懸濁液へ、ＮａＢＨ_４（１３．６５ｇ、３６１ｍｍｏｌ）を少しずつ添加した。この反応混合物を、室温にて一晩攪拌し、ろ過し、ＤＣＭ（１Ｌ）で洗浄した。有機相を、飽和ＮａＨＣＯ_３（２００ｍＬ）で、次に鹹水で洗浄し、無水Ｎａ_２ＳＯ_４上で乾燥し、濃縮して、表題の化合物を褐色液体として得た（２６ｇ、収率５０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ＭＳシグナルなし、１．７０分（保持時間）

(E) -1-Chloro-4- (4- (2-nitrovinyl) phenoxy) -2- (trifluoromethyl) benzene (13 g, 43.2 mmol) in i-PrOH (155 mL) and CHCl ₃ (465 mL) And NaBH ₄ (13.65 g, 361 mmol) was added in portions to a suspension of silica gel (120 g, 100-200 mesh). The reaction mixture was stirred at room temperature overnight, filtered and washed with DCM (1 L). The organic phase was washed with saturated NaHCO ₃ (200 mL), then brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a brown liquid (26 g, 50% yield). .
LC-MS (ESI): no MS signal, 1.70 minutes (retention time)

D22: 2- (4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenyl) ethanamine

メタノール（２５０ｍＬ）および水（２５０ｍＬ）中の１‐クロロ‐４‐（４‐（２‐ニトロエチル）フェノキシ）‐２‐（トリフルオロメチル）ベンゼン（２１ｇ、６０．７ｍｍｏｌ）およびギ酸アンモニウム（３０．６ｇ、４８６ｍｍｏｌ）の溶液へ、亜鉛粉末（１５．８９ｇ、２４３ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌し、ガラスグリット（glass grit）を通してろ過し、メタノールで洗浄した。ろ液を濃縮し、残渣をＤＣＭ（２００ｍＬ）で抽出し、次に飽和ＮａＨＣＯ_３（１００ｍＬ）、鹹水で洗浄し、無水Ｎａ_２ＳＯ_４上で乾燥し、濃縮した。ＦＣ（ＤＣＭ／ＣＨ_３ＯＨ＝１００／８）で精製して、表題の化合物を黄色オイルとして得た（７．０ｇ）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１６［Ｍ＋Ｈ］^＋、１．１５分（保持時間）

1-chloro-4- (4- (2-nitroethyl) phenoxy) -2- (trifluoromethyl) benzene (21 g, 60.7 mmol) and ammonium formate (30.6 g) in methanol (250 mL) and water (250 mL) , 486 mmol), zinc powder (15.89 g, 243 mmol) was added. The reaction mixture was stirred at 80 ° C. for 2 hours, filtered through glass grit and washed with methanol. The filtrate was concentrated and the residue was extracted with DCM (200 mL), then washed with saturated NaHCO ₃ (100 mL), brine, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by FC (DCM / CH ₃ OH = 100/8) gave the title compound as a yellow oil (7.0 g).
LC-MS (ESI): m / z 316 [M + H] ⁺ , 1.15 minutes (retention time)

D23: 3-Fluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、４‐フルオロ‐３‐（トリフルオロメチル）フェノールおよび３，４‐ジフルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０３［Ｍ＋Ｈ］^＋、３．６５分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-fluoro-3- (trifluoromethyl) phenol and 3,4-difluorobenzaldehyde.
LC-MS (ESI): m / z 303 [M + H] ⁺ , 3.65 minutes (retention time)

D24: (3-Fluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（４‐フルオロ‐３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ−１７］^＋、３．３２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 287 [M-17] ⁺ , 3.32 minutes (retention time)

D25: 4- (3,4-Difluorophenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロフェノールおよび４‐フルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３５［Ｍ＋Ｈ］^＋、３．３８分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorophenol and 4-fluorobenzaldehyde.
LC-MS (ESI): m / z 235 [M + H] ⁺ , 3.38 minutes (retention time)

D26: (4- (3,4-difluorophenoxy) phenyl) methanol

表題の化合物を、４‐（３，４‐ジフルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２１９［Ｍ−１７］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3,4-difluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 219 [M-17] ⁺ , 3.02 minutes (retention time)

D27
4- (3-Chloro-4-fluorophenoxy) -3-fluorobenzaldehyde

表題の化合物を、３‐クロロ‐４‐フルオロフェノールおよび３，４‐ジフルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６９［Ｍ＋１］^＋、３．６０分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3-chloro-4-fluorophenol and 3,4-difluorobenzaldehyde.
LC-MS (ESI): m / z 269 [M + 1] ⁺ , 3.60 minutes (retention time)

D28
(4- (3-Chloro-4-fluorophenoxy) -3-fluorophenyl) methanol

表題の化合物を、４‐（３‐クロロ‐４‐フルオロフェノキシ）‐３‐フルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７１［Ｍ＋１］^＋、３．２０分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-chloro-4-fluorophenoxy) -3-fluorobenzaldehyde.
LC-MS (ESI): m / z 271 [M + 1] ⁺ , 3.20 minutes (retention time)

D29
4- (3-Chlorophenoxy) -3-fluorobenzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐クロロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５１［Ｍ＋１］^＋、３．５８分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3-chlorophenol.
LC-MS (ESI): m / z 251 [M + 1] ⁺ , 3.58 minutes (retention time)

D30
(4- (3-Chlorophenoxy) -3-fluorophenyl) methanol

表題の化合物を、４‐（３‐クロロフェノキシ）‐３‐フルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋１］^＋、３．２４分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-chlorophenoxy) -3-fluorobenzaldehyde.
LC-MS (ESI): m / z 253 [M + 1] ⁺ , 3.24 minutes (retention time)

D31
4- (3-Chloro-4-fluorophenoxy) benzaldehyde

表題の化合物を、４‐フルオロベンズアルデヒドおよび３‐クロロ‐４‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５１［Ｍ＋１］^＋、３．５８分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-fluorobenzaldehyde and 3-chloro-4-fluorophenol.
LC-MS (ESI): m / z 251 [M + 1] ⁺ , 3.58 minutes (retention time)

D32
(4- (3-Chloro-4-fluorophenoxy) phenyl) methanol

表題の化合物を、４‐（３‐クロロ‐４‐フルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋１］^＋、３．２０分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-chloro-4-fluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 253 [M + 1] ⁺ , 3.20 minutes (retention time)

D33
3-Fluoro-4- (3-fluorophenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３５［Ｍ＋１］^＋、３．３７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluorophenol.
LC-MS (ESI): m / z 235 [M + 1] ⁺ , 3.37 minutes (retention time)

D34
(3-Fluoro-4- (3-fluorophenoxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（３‐フルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２１９［Ｍ＋１］^＋、２．９９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4- (3-fluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 219 [M + 1] ⁺ , 2.99 minutes (retention time)

D35
4-phenoxybenzaldehyde

表題の化合物を、４‐フルオロベンズアルデヒドおよびフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ １９９［Ｍ＋１］^＋、３．０５分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-fluorobenzaldehyde and phenol.
LC-MS (ESI): m / z 199 [M + 1] ⁺ , 3.05 minutes (retention time)

D36
(4-Phenoxyphenyl) methanol

表題の化合物を、（４‐フェノキシフェニル）メタノールから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２０１［Ｍ＋１］^＋、２．８２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from (4-phenoxyphenyl) methanol.
LC-MS (ESI): m / z 201 [M + 1] ⁺ , 2.82 minutes (retention time)

D37
3-Fluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ＋１］^＋、３．６４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 285 [M + 1] ⁺ , 3.64 minutes (retention time)

D38
(3-Fluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ＋１］^＋、３．３０分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 287 [M + 1] ⁺ , 3.30 minutes (retention time)

D39
5-Formyl-2- (4- (trifluoromethyl) phenoxy) benzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび４‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９２［Ｍ＋１］^＋、３．４１分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 292 [M + 1] ⁺ , 3.41 min (retention time)

D40
5- (Hydroxymethyl) -2- (4- (trifluoromethyl) phenoxy) benzonitrile

表題の化合物を、５‐（ヒドロキシメチル）‐２‐（４‐（トリフルオロメチル）フェノキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９４［Ｍ＋１］^＋、３．１３分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 5- (hydroxymethyl) -2- (4- (trifluoromethyl) phenoxy) benzonitrile.
LC-MS (ESI): m / z 294 [M + 1] ⁺ , 3.13 minutes (retention time)

D41
2- (4-Fluorophenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび４‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４２［Ｍ＋１］^＋、３．１２分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-fluorophenol.
LC-MS (ESI): m / z 242 [M + 1] ⁺ , 3.12 minutes (retention time)

D42
2- (4-Fluorophenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（４‐フルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４４［Ｍ＋１］^＋、２．８０分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (4-fluorophenoxy) -5- (hydroxymethyl) benzonitrile.
LC-MS (ESI): m / z 244 [M + 1] ⁺ , 2.80 minutes (retention time)

D43
3-Fluoro-4-((6- (trifluoromethyl) pyridin-2-yl) oxy) benzaldehyde

表題の化合物を、３‐フルオロ‐４‐ヒドロキシベンズアルデヒドおよび２‐クロロ‐６‐（トリフルオロメチル）ピリジンから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８６［Ｍ＋Ｈ］^＋、３．３４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3-fluoro-4-hydroxybenzaldehyde and 2-chloro-6- (trifluoromethyl) pyridine.
LC-MS (ESI): m / z 286 [M + H] ⁺ , 3.34 minutes (retention time)

D44
(3-Fluoro-4-((6- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８８［Ｍ＋Ｈ］^＋、２．９８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4-((6- (trifluoromethyl) pyridin-2-yl) oxy) benzaldehyde.
LC-MS (ESI): m / z 288 [M + H] ⁺ , 2.98 minutes (retention time)

D45
3-Fluoro-5- (hydroxymethyl) benzonitrile

表題の化合物を、メチル３‐シアノ‐５‐フルオロベンゾエートから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ １５２［Ｍ＋１］^＋、１．８４分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from methyl 3-cyano-5-fluorobenzoate.
LC-MS (ESI): m / z 152 [M + 1] ⁺ , 1.84 minutes (retention time)

D46
2- (3,4-Difluorophenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび３，４‐ジフルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６０［Ｍ＋１］^＋、３．１５分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3,4-difluorophenol.
LC-MS (ESI): m / z 260 [M + 1] ⁺ , 3.15 minutes (retention time)

D47
2- (3,4-Difluorophenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（３，４‐ジフルオロフェノキシ）‐５‐ホルミルベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６２［Ｍ＋１］^＋、２．８６分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (3,4-difluorophenoxy) -5-formylbenzonitrile.
LC-MS (ESI): m / z 262 [M + 1] ⁺ , 2.86 minutes (retention time)

D48
5-Bromo-2- (3,4-difluorophenoxy) pyridine

ジメチルスルホキシド（ＤＭＳＯ）（１５０ｍＬ）中の５‐ブロモ‐２‐フルオロピリジン（１９ｇ、１０８ｍｍｏｌ）および３，４‐ジフルオロフェノール（１４．０５ｇ、１０８ｍｍｏｌ）の溶液へ、炭酸カリウム（２６．９ｇ、１９４ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌し、次に、Ｈ_２Ｏ（２００ｍＬ）およびＥｔＯＡｃ（２００ｍＬ）を添加した。有機層を分離し、次に減圧濃縮した。粗生成物を、Ｈｅｘ／ＥｔＯＡｃ（１０：１）で溶出するシリカゲルクロマトグラフィで精製して、５‐ブロモ‐２‐（３，４‐ジフルオロフェノキシ）ピリジンを得た（１９ｇ、５５．４％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８６［Ｍ＋１］^＋、１．２５分（保持時間）

To a solution of 5-bromo-2-fluoropyridine (19 g, 108 mmol) and 3,4-difluorophenol (14.05 g, 108 mmol) in dimethyl sulfoxide (DMSO) (150 mL), potassium carbonate (26.9 g, 194 mmol). Was added. The reaction mixture was stirred at 80 ° C. for 2 h, then H ₂ O (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex / EtOAc (10: 1) to give 5-bromo-2- (3,4-difluorophenoxy) pyridine (19 g, 55.4%).
LC-MS (ESI): m / z 286 [M + 1] ⁺ , 1.25 minutes (retention time)

D49
2- (3,4-Difluorophenoxy) -5-iodopyridine

テトラヒドロフラン（ＴＨＦ）（２００ｍＬ）中の５‐ブロモ‐２‐（３，４‐ジフルオロフェノキシ）ピリジン（１９ｇ、６６．４ｍｍｏｌ）の溶液へ、塩化イソプロピルマグネシウム（６６．４ｍＬ、６６．４ｍｍｏｌ）を添加した。この反応混合物を、２０℃にて２時間攪拌し、次に、Ｉ_２（１６．８６ｇ、６６．４ｍｍｏｌ）を添加した。この反応混合物を、２０℃にてさらに４時間攪拌し、次に、飽和ＮＨ_４Ｃｌ水溶液（２００ｍＬ）およびＥｔＯＡｃ（２００ｍＬ）を添加し、有機層を分離し、減圧濃縮した。粗生成物を、Ｈｅｘ／ＥｔＯＡｃ（２０：１）で溶出するシリカゲルクロマトグラフィで精製した。回収した画分から、２‐（３，４‐ジフルオロフェノキシ）‐５‐ヨードピリジンを得た（２２ｇ、６１．７％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３４［Ｍ＋Ｈ］^＋、１．２５分（保持時間）

To a solution of 5-bromo-2- (3,4-difluorophenoxy) pyridine (19 g, 66.4 mmol) in tetrahydrofuran (THF) (200 mL) was added isopropylmagnesium chloride (66.4 mL, 66.4 mmol). . The reaction mixture was stirred at 20 ° C. for 2 hours, then I ₂ (16.86 g, 66.4 mmol) was added. The reaction mixture was stirred at 20 ° C. for a further 4 hours, then saturated aqueous NH ₄ Cl (200 mL) and EtOAc (200 mL) were added, the organic layer was separated and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with Hex / EtOAc (20: 1). 2- (3,4-Difluorophenoxy) -5-iodopyridine was obtained from the collected fractions (22 g, 61.7%).
LC-MS (ESI): m / z 334 [M + H] ⁺ , 1.25 minutes (retention time)

D50
Diethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) malonate

１，４‐ジオキサン（２００ｍＬ）中の２‐（３，４‐ジフルオロフェノキシ）‐５‐ヨードピリジン（２２ｇ、４１．０ｍｍｏｌ）、マロン酸ジエチル（６．５６ｇ、４１．０ｍｍｏｌ）、およびＣｓ_２ＣＯ_３（１３．３４ｇ、４１．０ｍｍｏｌ）の懸濁液へ、ピコリン酸（５．０４ｇ、４１．０ｍｍｏｌ）およびヨウ化銅（Ｉ）（７．８０ｇ、４１．０ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて１０時間攪拌し、次に減圧濃縮した。残渣を、ＣＨ_２Ｃｌ_２で抽出し、次に、有機層を分離し、減圧濃縮して、ジエチル２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）マロネートを得た（２５ｇ、８５％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３６６［Ｍ＋Ｈ］^＋、１．２３分（保持時間）

2- (3,4-Difluorophenoxy) -5-iodopyridine (22 g, 41.0 mmol), diethyl malonate (6.56 g, 41.0 mmol), and Cs ₂ CO in 1,4-dioxane (200 mL) ₃ (13.34 g, 41.0 mmol) was added picolinic acid (5.04 g, 41.0 mmol) and copper (I) iodide (7.80 g, 41.0 mmol). The reaction mixture was stirred at 80 ° C. for 10 hours and then concentrated under reduced pressure. The residue was extracted with CH ₂ Cl ₂ , then the organic layer was separated and concentrated in vacuo to give diethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) malonate ( 25 g, 85%).
LC-MS (ESI): m / z 366 [M + H] ⁺ , 1.23 minutes (retention time)

D51
2- (6- (3,4-Difluorophenoxy) pyridin-3-yl) acetic acid

エタノール（２５０ｍＬ）中のジエチル２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）マロネート（２５ｇ、３４．９ｍｍｏｌ）の溶液へ、水酸化カリウム（１９．５８ｇ、３４９ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて１時間攪拌し、次に、この反応混合物を、減圧濃縮した。残渣に１０％ ＨＣｌを添加して、溶液を約ｐＨ７に調節した。次に、この溶液を、ＥｔＯＡｃ（３００ｍＬ）で抽出し、有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、次に減圧濃縮して、２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）酢酸を得た（１０ｇ、９８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６６［Ｍ＋Ｈ］^＋、１．０１分（保持時間）

To a solution of diethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) malonate (25 g, 34.9 mmol) in ethanol (250 mL) was added potassium hydroxide (19.58 g, 349 mmol). did. The reaction mixture was stirred at 80 ° C. for 1 hour and then the reaction mixture was concentrated in vacuo. 10% HCl was added to the residue to adjust the solution to about pH7. The solution is then extracted with EtOAc (300 mL) and the organic layer is separated, dried over Na ₂ SO ₄ and then concentrated under reduced pressure to give 2- (6- (3,4-difluorophenoxy). Pyridin-3-yl) acetic acid was obtained (10 g, 98%).
LC-MS (ESI): m / z 266 [M + H] ⁺ , 1.01 minutes (retention time)

D52
Ethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) acetate

エタノール（１００ｍＬ）中の２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）酢酸（１０ｇ、３７．７ｍｍｏｌ）の溶液へ、エタノール（１００ｍＬ）中の硫酸（２０ｍＬ、３７５ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて３時間攪拌し、次に、この反応混合物を、Ｎａ_２ＣＯ_３でアルカリ性とし、続いてＣＨ_２Ｃｌ_２で抽出した。有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、次に減圧濃縮して、エチル２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）アセテートを得た（１０ｇ、７８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９４［Ｍ＋Ｈ］^＋、１．１７分（保持時間）

To a solution of 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) acetic acid (10 g, 37.7 mmol) in ethanol (100 mL) was added sulfuric acid (20 mL, 375 mmol) in ethanol (100 mL). Added. The reaction mixture was stirred at 80 ° C. for 3 hours, then the reaction mixture was made alkaline with Na ₂ CO ₃ followed by extraction with CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ and then concentrated in vacuo to give ethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) acetate (10 g, 78 %).
LC-MS (ESI): m / z 294 [M + H] ⁺ , 1.17 minutes (retention time)

D53
2- (6- (3,4-Difluorophenoxy) pyridin-3-yl) ethanol

表題の化合物を、エチル２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）アセテートから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５２［Ｍ＋Ｈ］^＋、０．９９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from ethyl 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) acetate.
LC-MS (ESI): m / z 252 [M + H] ⁺ , 0.99 minutes (retention time)

D54
5-(((2,6-dichloropyrimidin-4-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile

Ｎ，Ｎ‐ジメチルホルムアミド（６ｍＬ）中のＮａＨ（０．５３２ｇ、１３．３０ｍｍｏｌ）の懸濁液へ、２，４，６‐トリクロロピリミジン（１．０５７ｇ、５．７６ｍｍｏｌ）を０℃にて添加した。この反応混合物を、室温にて５分間攪拌し、次に、Ｎ，Ｎ‐ジメチルホルムアミド（６ｍＬ）中の５‐（ヒドロキシメチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリル（１．３ｇ、４．４３ｍｍｏｌ）の溶液へ滴下した。この反応混合物を、室温にてさらに１時間攪拌した。次に、この反応混合物を、水で反応停止し、この溶液を、水／ＭｅＣＮを溶出液として用いた逆相カラムクロマトグラフィ（１２０ｇ）で精製して、５‐（（（２，６‐ジクロロピリミジン‐４‐イル）オキシ）メチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリルを得た（１．４ｇ、３．１８ｍｍｏｌ、収率７１．７％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４０［Ｍ＋１］^＋、４．１１分（保持時間）

To a suspension of NaH (0.532 g, 13.30 mmol) in N, N-dimethylformamide (6 mL) was added 2,4,6-trichloropyrimidine (1.057 g, 5.76 mmol) at 0 ° C. did. The reaction mixture was stirred at room temperature for 5 minutes, then 5- (hydroxymethyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile (1 in N, N-dimethylformamide (6 mL). 3 g, 4.43 mmol). The reaction mixture was stirred for an additional hour at room temperature. The reaction mixture was then quenched with water and the solution was purified by reverse phase column chromatography (120 g) using water / MeCN as the eluent to give 5-(((2,6-dichloropyrimidine. -4-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile was obtained (1.4 g, 3.18 mmol, yield 71.7%).
LC-MS (ESI): m / z 440 [M + 1] ⁺ , 4.11 min (retention time)

D55
5-(((6-((3-bromopropyl) amino) -2-chloropyrimidin-4-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile

Ｎ，Ｎ‐ジメチルホルムアミド（３ｍＬ）中の５‐（（（２，６‐ジクロロピリミジン‐４‐イル）オキシ）メチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリル（６００ｍｇ、１．３６３ｍｍｏｌ）およびＤＩＰＥＡ（１．５ｍＬ、８．５９ｍｍｏｌ）の溶液へ、０℃にて３‐ブロモプロパン‐１‐アミン臭化水素酸塩（９００ｍｇ、４．１１ｍｍｏｌ）を添加し、この反応混合物を、０℃にて一晩攪拌した。この溶液を、水（０．３％ ＴＦＡ含有）およびＭｅＣＮを溶出液として用いた逆相カラムクロマトグラフィ（１２０ｇ）で精製して、５‐（（（６‐（（３‐ブロモプロピル）アミノ）‐２‐クロロピリミジン‐４‐イル）オキシ）メチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリルを得た（３５０ｍｇ、０．６４６ｍｍｏｌ、収率４７．４％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６１［Ｍ＋１］^＋、３．００分（保持時間）

5-(((2,6-dichloropyrimidin-4-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile (600 mg, 1 in N, N-dimethylformamide (3 mL) .363 mmol) and DIPEA (1.5 mL, 8.59 mmol) at 0 ° C. was added 3-bromopropan-1-amine hydrobromide (900 mg, 4.11 mmol) and the reaction mixture was And stirred at 0 ° C. overnight. The solution was purified by reverse phase column chromatography (120 g) using water (containing 0.3% TFA) and MeCN as eluent to give 5-((((6-((3-bromopropyl) amino)- 2-Chloropyrimidin-4-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile was obtained (350 mg, 0.646 mmol, 47.4% yield).
LC-MS (ESI): m / z 461 [M + 1] ⁺ , 3.00 minutes (retention time)

D56
5- (4-Chloro-3- (trifluoromethyl) phenoxy) -2-nitropyridine

アセトニトリル（２００ｍＬ）中の５‐ブロモ‐２‐ニトロピリジン（１５ｇ、７３．９ｍｍｏｌ）および４‐クロロ‐３‐（トリフルオロメチル）フェノール（１４．５２ｇ、７３．９ｍｍｏｌ）の溶液へ、炭酸カリウム（１８．３８ｇ、１３３ｍｍｏｌ）を添加し、この反応混合物を、８０℃にて１０時間攪拌した。次に、２００ｍＬのＥｔＯＡｃおよび２００ｍＬのＨ_２Ｏを添加した。有機層を分離し、減圧濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィで精製し、Ｈｅｘ／ＥｔＯＡｃ（５：１）で溶出して、５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）‐２‐ニトロピリジンを得た（８ｇ、３２．８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１９［Ｍ＋１］^＋、１．２３分（保持時間）

To a solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) and 4-chloro-3- (trifluoromethyl) phenol (14.52 g, 73.9 mmol) in acetonitrile (200 mL) was added potassium carbonate ( 18.38 g, 133 mmol) was added and the reaction mixture was stirred at 80 ° C. for 10 hours. Then 200 mL EtOAc and 200 mL H ₂ O were added. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with Hex / EtOAc (5: 1) to give 5- (4-chloro-3- (trifluoromethyl) phenoxy) -2-nitropyridine ( 8g, 32.8%).
LC-MS (ESI): m / z 319 [M + 1] ⁺ , 1.23 minutes (retention time)

D57
5- (4-Chloro-3- (trifluoromethyl) phenoxy) pyridin-2-amine

エタノール（１００ｍＬ）中の５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）‐２‐ニトロピリジン（８ｇ、２５．１ｍｍｏｌ）の溶液へ、塩化スズ（ＩＩ）二水和物（５６．７ｇ、２５１ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌し、５００ｍＬのＨ_２Ｏへ注ぎ入れ、１０％ ＮａＨＣＯ_３を用いて塩基性に調節した。次に、この反応混合物を、５００ｍＬのＥｔＯＡｃで抽出した。有機層を分離し、次に、Ｎａ_２ＳＯ_４上で乾燥し、減圧濃縮して、５‐（４‐クロロ‐３‐（トリフルオロメチル）‐フェノキシ）ピリジン‐２‐アミンを得た（６ｇ、７２．９％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋１］^＋、０．９８分（保持時間）

To a solution of 5- (4-chloro-3- (trifluoromethyl) phenoxy) -2-nitropyridine (8 g, 25.1 mmol) in ethanol (100 mL), tin (II) chloride dihydrate (56. 7 g, 251 mmol) was added. The reaction mixture was stirred at 80 ° C. for 2 hours, poured into 500 mL H ₂ O and adjusted to basic with 10% NaHCO ₃ . The reaction mixture was then extracted with 500 mL of EtOAc. The organic layer was separated then dried over Na ₂ SO _{4 and} concentrated in vacuo to give 5- (4-chloro-3- (trifluoromethyl) -phenoxy) pyridin-2-amine (6 g 72.9%).
LC-MS (ESI): m / z 289 [M + 1] ⁺ , 0.98 minutes (retention time)

D58
5- (4-Chloro-3- (trifluoromethyl) phenoxy) -2-iodopyridine

ジヨードメタン（５０ｇ、１８７ｍｍｏｌ）中の５‐（４‐クロロ‐３‐（トリフルオロメチル）‐フェノキシ）ピリジン‐２‐アミン（６ｇ、２０．７９ｍｍｏｌ）の懸濁液へ、亜硝酸イソアミル（１３．９９ｍＬ、１０４ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌した。粗生成物を、Ｈｅｘ／ＥｔＯＡｃ（２０：１）で溶出するシリカゲルカラムで精製して、粗５‐（４‐クロロ‐３‐トリフルオロメチル）フェノキシ）‐２‐ヨードピリジンを得た（６ｇ、３４．０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋１］^＋、１．３２分（保持時間）

To a suspension of 5- (4-chloro-3- (trifluoromethyl) -phenoxy) pyridin-2-amine (6 g, 20.79 mmol) in diiodomethane (50 g, 187 mmol), isoamyl nitrite (13.99 mL). , 104 mmol). The reaction mixture was stirred at 80 ° C. for 2 hours. The crude product was purified on a silica gel column eluted with Hex / EtOAc (20: 1) to give crude 5- (4-chloro-3-trifluoromethyl) phenoxy) -2-iodopyridine (6 g, 34.0%).
LC-MS (ESI): m / z 289 [M + 1] ⁺ , 1.32 minutes (retention time)

D59
Diethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) malonate

１，４‐ジオキサン（６０ｍＬ）中の５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）‐２‐ヨードピリジン（６ｇ、７．０６ｍｍｏｌ）、マロン酸ジエチル（２．２６１ｇ、１４．１２ｍｍｏｌ）、およびピコリン酸（０．２６１ｇ、２．１１７ｍｍｏｌ）の溶液へ、Ｃｓ_２ＣＯ_３（６．９０ｇ、２１．１７ｍｍｏｌ）およびヨウ化銅（Ｉ）（０．１３４ｇ、０．７０６ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて１０時間攪拌し、次に減圧濃縮した。この反応混合物を、次に、ＣＨ_２Ｃｌ_２で抽出した。有機層を分離し、減圧濃縮して、ジエチル２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）マロネートを得た（６ｇ、７７％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３２［Ｍ＋１］^＋、１．４８分（保持時間）

5- (4-Chloro-3- (trifluoromethyl) phenoxy) -2-iodopyridine (6 g, 7.06 mmol), diethyl malonate (2.261 g, 14.12 mmol) in 1,4-dioxane (60 mL) ) And picolinic acid (0.261 g, 2.117 mmol) were added Cs ₂ CO ₃ (6.90 g, 21.17 mmol) and copper (I) iodide (0.134 g, 0.706 mmol). . The reaction mixture was stirred at 80 ° C. for 10 hours and then concentrated under reduced pressure. The reaction mixture was then extracted with CH ₂ Cl ₂ . The organic layer was separated and concentrated in vacuo to give diethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) malonate (6 g, 77%).
LC-MS (ESI): m / z 432 [M + 1] ⁺ , 1.48 minutes (retention time)

D60
2- (5- (4-Chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) acetic acid

エタノール（６０ｍＬ）中のジエチル２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）マロネート（６ｇ、５．４２ｍｍｏｌ）の溶液へ、水酸化カリウム（３．０４ｇ、５４．２ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて１時間攪拌し、次に減圧濃縮した。１０％ ＨＣｌ水溶液を用いて、この反応混合物をｐＨ７に調節した。この反応混合物を、１００ｍＬのＥｔＯＡｃで抽出し、有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、次に減圧濃縮して、２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）酢酸を得た（３ｇ、１００％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３２［Ｍ＋１］^＋、１．１０分（保持時間）

To a solution of diethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) malonate (6 g, 5.42 mmol) in ethanol (60 mL) was added potassium hydroxide (3. 04 g, 54.2 mmol) was added. The reaction mixture was stirred at 80 ° C. for 1 hour and then concentrated under reduced pressure. The reaction mixture was adjusted to pH 7 using 10% aqueous HCl. The reaction mixture is extracted with 100 mL of EtOAc, the organic layer is separated, dried over Na ₂ SO ₄ and then concentrated under reduced pressure to give 2- (5- (4-chloro-3- (trifluoromethyl). ) Phenoxy) pyridin-2-yl) acetic acid was obtained (3 g, 100%).
LC-MS (ESI): m / z 332 [M + 1] ⁺ , 1.10 minutes (retention time)

D61
Ethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) acetate

エタノール（３０ｍＬ）中の２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）酢酸（３ｇ、５．６１ｍｍｏｌ）の溶液へ、エタノール（３０ｍＬ）中の硫酸（８ｍＬ、１５０ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌した。次に、この反応混合物に、３０ｍＬの２５％ ＮＨ_４ＯＨ水溶液および５０ｍＬのＣＨ_２Ｃｌ_２を添加した。有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、減圧濃縮して、エチル２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）アセテートを得た（２ｇ、７９％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３６０［Ｍ＋１］^＋、１．２４分（保持時間）

To a solution of 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) acetic acid (3 g, 5.61 mmol) in ethanol (30 mL), sulfuric acid in ethanol (30 mL) (8 mL, 150 mmol) was added. The reaction mixture was stirred at 80 ° C. for 2 hours. To the reaction mixture was then added 30 mL of 25% aqueous NH ₄ OH and 50 mL of CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO _{4 and} concentrated under reduced pressure to give ethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) acetate. (2 g, 79%).
LC-MS (ESI): m / z 360 [M + 1] ⁺ , 1.24 minutes (retention time)

D62
2- (5- (4-Chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanol

エタノール（２０ｍＬ）中のエチル２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）アセテート（２ｇ、４．４５ｍｍｏｌ）の溶液へ、水素化ホウ素ナトリウム（１．６８３ｇ、４４．５ｍｍｏｌ）を添加した。この反応混合物を、２０℃にて１０時間攪拌した。この反応混合物に、５０ｍＬのＨ_２Ｏおよび５０ｍＬのＣＨ_２Ｃｌ_２を添加した。有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、減圧濃縮した。粗生成物を、ＭｅＣＮ／ＴＦＡ ０．１％で溶出する分取用ＨＰＬＣカラムに投入して、２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）エタノールを得た（５００ｍｇ、２５．５％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１８［Ｍ＋１］^＋、１．００分（保持時間）

To a solution of ethyl 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) acetate (2 g, 4.45 mmol) in ethanol (20 mL) was added sodium borohydride (1 683 g, 44.5 mmol) was added. The reaction mixture was stirred at 20 ° C. for 10 hours. To this reaction mixture was added 50 mL H ₂ O and 50 mL CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO _{4 and} concentrated under reduced pressure. The crude product was loaded onto a preparative HPLC column eluting with MeCN / TFA 0.1% and 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) Ethanol was obtained (500 mg, 25.5%).
LC-MS (ESI): m / z 318 [M + 1] ⁺ , 1.00 min (retention time)

D63
4-{[4-Chloro-3- (trifluoromethyl) phenyl] oxy} benzaldehyde

表題の化合物を、４‐フルオロベンズアルデヒドおよび４‐クロロ‐３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０１［Ｍ＋Ｈ］^＋、３．７６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-fluorobenzaldehyde and 4-chloro-3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 301 [M + H] ⁺ , 3.76 minutes (retention time)

D64
4-Chloro-3- (trifluoromethyl) phenyl 4-ethenylphenyl ether

無水テトラヒドロフラン（ＴＨＦ）（５０ｍＬ）中の臭化メチル（トリフェニル）ホスホニウム（５．５６ｇ、１５．５７ｍｍｏｌ）の懸濁液へ、０℃にてＢｕＬｉ（９．５ｍＬ、１５．２０ｍｍｏｌ）を滴下した。反応混合物が透明溶液となった後、これを０℃にて１５分間攪拌し、次に、ＴＨＦ（１０ｍＬ）中の４‐｛［４‐クロロ‐３‐（トリフルオロメチル）フェニル］オキシ｝ベンズアルデヒド（４．０７ｇ、１３．５４ｍｍｏｌ）の溶液を添加した。この反応混合物を、室温まで加温し、１時間攪拌した。この混合物を、飽和ＮＨ_４Ｃｌで反応停止し、次に濃縮した。残渣を酢酸エチル（１００ｍＬ）に溶解し、水および鹹水で洗浄した。この混合物を、無水硫酸ナトリウム上で乾燥し、濃縮した。ＩＳＣＯで精製して、表題の化合物を得た（３．０ｇ）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９９［Ｍ−Ｈ］^＋、５．０７分（保持時間）

To a suspension of methyl (triphenyl) phosphonium bromide (5.56 g, 15.57 mmol) in anhydrous tetrahydrofuran (THF) (50 mL), BuLi (9.5 mL, 15.20 mmol) was added dropwise at 0 ° C. . After the reaction mixture became a clear solution, it was stirred for 15 minutes at 0 ° C. and then 4-{[4-chloro-3- (trifluoromethyl) phenyl] oxy} benzaldehyde in THF (10 mL). A solution of (4.07 g, 13.54 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched with saturated NH ₄ Cl and then concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Purification by ISCO gave the title compound (3.0 g).
LC-MS (ESI): m / z 299 [M−H] ⁺ , 5.07 minutes (retention time)

D65
2- (4-{[4-Chloro-3- (trifluoromethyl) phenyl] oxy} phenyl) ethanol

無水テトラヒドロフラン（５０ｍＬ）中の１‐クロロ‐４‐［（４‐エテニルフェニル）オキシ］‐２‐（トリフルオロメチル）ベンゼン（３．８ｇ、１２．７２ｍｍｏｌ）の混合物へ、９‐ＢＢＮ（５０．９ｍＬ、２５．４ｍｍｏｌ）を０℃にて滴下した。この反応混合物を、室温にて一晩攪拌し、次に、水酸化ナトリウム（４２．４ｍＬ、１２７ｍｍｏｌ）およびＨ_２Ｏ_２（２．６０ｍＬ、２５．４ｍｍｏｌ）を０℃にて添加した。この反応混合物を、５０℃にて２時間攪拌し、水性Ｎａ_２ＳＯ_３で反応停止し、続いて濃縮した。質量分析付き自動分取により精製して、表題の化合物を得た（２．０ｇ）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１７［Ｍ＋Ｈ］^＋、３．５６分（保持時間）

To a mixture of 1-chloro-4-[(4-ethenylphenyl) oxy] -2- (trifluoromethyl) benzene (3.8 g, 12.72 mmol) in anhydrous tetrahydrofuran (50 mL), 9-BBN (50 .9 mL, 25.4 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight, then sodium hydroxide (42.4 mL, 127 mmol) and H ₂ O ₂ (2.60 mL, 25.4 mmol) were added at 0 ° C. The reaction mixture was stirred at 50 ° C. for 2 hours, quenched with aqueous Na ₂ SO ₃ and subsequently concentrated. Purification by automatic fractionation with mass spectrometry gave the title compound (2.0 g).
LC-MS (ESI): m / z 317 [M + H] ⁺ , 3.56 minutes (retention time)

D66
5-Formyl-2-((6-methylpyridin-3-yl) oxy) benzonitrile

表題の化合物を、６‐メチル‐３‐ピリジノールおよび２‐フルオロ‐５‐ホルミルベンゾニトリルから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３９［Ｍ＋Ｈ］^＋、１．７４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 6-methyl-3-pyridinol and 2-fluoro-5-formylbenzonitrile.
LC-MS (ESI): m / z 239 [M + H] ⁺ , 1.74 minutes (retention time)

D67
5- (Hydroxymethyl) -2-((6-methylpyridin-3-yl) oxy) benzonitrile

表題の化合物を、５‐ホルミル‐２‐（（６‐メチルピリジン‐３‐イル）オキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４１［Ｍ＋Ｈ］^＋、１．４５分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 5-formyl-2-((6-methylpyridin-3-yl) oxy) benzonitrile.
LC-MS (ESI): m / z 241 [M + H] ⁺ , 1.45 minutes (retention time)

D68
4-((6- (Trifluoromethyl) pyridin-2-yl) oxy) benzaldehyde

表題の化合物を、２‐クロロ‐６‐（トリフルオロメチル）ピリジンおよび４‐ヒドロキシベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６８［Ｍ＋Ｈ］^＋、３．２６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-chloro-6- (trifluoromethyl) pyridine and 4-hydroxybenzaldehyde.
LC-MS (ESI): m / z 268 [M + H] ⁺ , 3.26 minutes (retention time)

D69
2- (Trifluoromethyl) -6- (4-vinylphenoxy) pyridine

表題の化合物を、４‐（（６‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）ベンズアルデヒドから出発して、Ｄ６４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６６［Ｍ＋Ｈ］^＋、３．７９分（保持時間）

The title compound was made in a similar procedure as described for D64 starting from 4-((6- (trifluoromethyl) pyridin-2-yl) oxy) benzaldehyde.
LC-MS (ESI): m / z 266 [M + H] ⁺ , 3.79 minutes (retention time)

D70
2- (4-((6- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) ethanol

表題の化合物を、２‐（トリフルオロメチル）‐６‐（４‐ビニルフェノキシ）ピリジンから出発して、Ｄ６５についての記載に類似の手順で作製した。

The title compound was made in a similar procedure as described for D65 starting from 2- (trifluoromethyl) -6- (4-vinylphenoxy) pyridine.

D71
4- (3,5-Difluorophenoxy) -3-fluorobenzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３，５‐トリフルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋Ｈ］^＋、２．６６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3,5-trifluorophenol.
LC-MS (ESI): m / z 253 [M + H] ⁺ , 2.66 minutes (retention time)

D72
(4- (3,5-Difluorophenoxy) -3-fluorophenyl) methanol

表題の化合物を、４‐（３，５‐ジフルオロフェノキシ）‐３‐フルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３７［Ｍ＋Ｈ］^＋、３．１３分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3,5-difluorophenoxy) -3-fluorobenzaldehyde.
LC-MS (ESI): m / z 237 [M + H] ⁺ , 3.13 minutes (retention time)

D73
1-Chloro-4- (4-ethynylphenoxy) -2- (trifluoromethyl) benzene

メタノール（３０ｍＬ）中の（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒド（１．８２ｇ、６．０ｍｍｏｌ）およびジメチル（１‐ジアゾ‐２‐オキソプロピル）ホスホネート（２．３ｇ、１２．１ｍｍｏｌ）の溶液へ、炭酸カリウム（４．１８ｇ、３０．３ｍｍｏｌ）を添加し、室温にて１時間攪拌した。この反応混合物を濃縮し、残渣をＦＣ（ＰＥ／ＥｔＯＡｃ ２０：１）で精製して、表題の化合物を無色オイルとして得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９７［Ｍ＋Ｈ］^＋、４．１４分（保持時間）

(4-Chloro-3- (trifluoromethyl) phenoxy) benzaldehyde (1.82 g, 6.0 mmol) and dimethyl (1-diazo-2-oxopropyl) phosphonate (2.3 g, 12.12) in methanol (30 mL). To the 1 mmol) solution, potassium carbonate (4.18 g, 30.3 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by FC (PE / EtOAc 20: 1) to give the title compound as a colorless oil.
LC-MS (ESI): m / z 297 [M + H] ⁺ , 4.14 minutes (retention time)

D74
8-((4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenyl) ethynyl) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

無水ＴＨＦ（１２ｍＬ）中の塩化ビス（トリフェニルホスフィン）パラジウム（ＩＩ）（７０．３ｍｇ、０．１ｍｍｏｌ）およびヨウ化銅（Ｉ）（１９．１ｍｇ、０．１ｍｍｏｌ）の懸濁液を、室温にて１０分間、Ａｒでパージした。この懸濁液を、トリエチルアミン（０．４２ｍＬ、３．０ｍｍｏｌ）で処理し、１‐クロロ‐４‐（４‐エチニルフェノキシ）‐２‐（トリフルオロメチル）ベンゼン（４４６ｍｇ、１．５ｍｍｏｌ）を、Ａｒ雰囲気下にて添加すると、暗琥珀色となった。５分後、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（１００ｍｇ、０．５ｍｍｏｌ）を添加し、５０℃にて２時間攪拌した。この反応混合物を、ＥｔＯＡｃで希釈し、水で洗浄し、続いて濃縮した。残渣をＭＤＡＰで精製して、表題の化合物（３０ｍｇ）を淡黄色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６０［Ｍ＋Ｈ］^＋、３．１分（保持時間）

A suspension of bis (triphenylphosphine) palladium (II) chloride (70.3 mg, 0.1 mmol) and copper (I) iodide (19.1 mg, 0.1 mmol) in anhydrous THF (12 mL) was added at room temperature. And purged with Ar for 10 minutes. This suspension was treated with triethylamine (0.42 mL, 3.0 mmol) and 1-chloro-4- (4-ethynylphenoxy) -2- (trifluoromethyl) benzene (446 mg, 1.5 mmol) was When added in an Ar atmosphere, it became a dark blue color. After 5 minutes, 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (100 mg, 0.5 mmol) was added and brought to 50 ° C. And stirred for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and subsequently concentrated. The residue was purified by MDAP to give the title compound (30 mg) as a pale yellow solid.
LC-MS (ESI): m / z 460 [M + H] ⁺ , 3.1 minutes (retention time)

D75
3-Fluoro-4- (4-fluorophenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび４‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３５［Ｍ＋Ｈ］^＋、３．３３分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 4-fluorophenol.
LC-MS (ESI): m / z 235 [M + H] ⁺ , 3.33 minutes (retention time)

D76
(3-Fluoro-4- (4-fluorophenoxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（４‐フルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２１９［Ｍ−１７］^＋、２．９５分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4- (4-fluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 219 [M-17] ⁺ , 2.95 minutes (retention time)

D77
5- (Hydroxymethyl) -2- (3-pyridinyloxy) benzonitrile

表題の化合物を、Ｄ４についての記載に類似の手順によりピリジン‐３‐オールと２‐フルオロ‐５‐ホルミルベンゾニトリルとの反応から作製した５‐ホルミル‐２‐（ピリジン‐３‐イルオキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２２７［Ｍ＋Ｈ］^＋、０．３１分（保持時間）

5-Formyl-2- (pyridin-3-yloxy) benzonitrile prepared from the reaction of pyridin-3-ol and 2-fluoro-5-formylbenzonitrile by a procedure similar to that described for D4 Prepared in a similar procedure as described for D5 starting from.
LC-MS (ESI): m / z 227 [M + H] ⁺ , 0.31 minutes (retention time)

D78
4-((3- (trifluoromethyl) oxy) phenyl) methanol

表題の化合物を、Ｄ４についての記載に類似の手順により４‐フルオロベンズアルデヒドと３‐（トリフルオロメチル）フェノールとの反応から作製した４‐（３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５１［Ｍ−１７］^＋、３．２４分（保持時間）

The title compound was started from 4- (3- (trifluoromethyl) phenoxy) benzaldehyde made from the reaction of 4-fluorobenzaldehyde with 3- (trifluoromethyl) phenol by a procedure similar to that described for D4. , Prepared in a similar procedure as described for D5.
LC-MS (ESI): m / z 251 [M-17] ⁺ , 3.24 minutes (retention time)

D79
3,5-Difluoro-4- (3-fluorophenoxy) benzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋Ｈ］^＋、３．４４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluorophenol.
LC-MS (ESI): m / z 253 [M + H] ⁺ , 3.44 minutes (retention time)

D80
(3,5-Difluoro-4- (3-fluorophenoxy) phenyl) methanol

表題の化合物を、３，５‐ジフルオロ‐４‐（３‐フルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５５［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3,5-difluoro-4- (3-fluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 255 [M + H] ⁺ , 3.02 minutes (retention time)

D81
4- (3,5-Difluorophenoxy) -3,5-difluorobenzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３，５‐ジフルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７１［Ｍ＋Ｈ］^＋、３．５４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,5-difluorophenol.
LC-MS (ESI): m / z 271 [M + H] ⁺ , 3.54 minutes (retention time)

D82
(4- (3,5-Difluorophenoxy) -3,5-difluorophenyl) methanol

表題の化合物を、４‐（３，５‐ジフルオロフェノキシ）‐３，５‐ジフルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７３［Ｍ＋Ｈ］^＋、３．２８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3,5-difluorophenoxy) -3,5-difluorobenzaldehyde.
LC-MS (ESI): m / z 273 [M + H] ⁺ , 3.28 minutes (retention time)

D83
2- (3-Fluorophenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび２‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４２［Ｍ＋Ｈ］^＋、３．１１分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluorophenol.
LC-MS (ESI): m / z 242 [M + H] ⁺ , 3.11 minutes (retention time)

D84
2- (3-Fluorophenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（３‐フルオロフェノキシ）‐５‐ホルミルベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４４［Ｍ＋Ｈ］^＋、２．７９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (3-fluorophenoxy) -5-formylbenzonitrile.
LC-MS (ESI): m / z 244 [M + H] ⁺ , 2.79 minutes (retention time)

D85
3,5-Difluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０５［Ｍ＋Ｈ］^＋、３．３６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 305 [M + H] ⁺ , 3.36 minutes (retention time)

D86
(3,5-Difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３，５‐ジフルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０５［Ｍ＋Ｈ］^＋、３．３６分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 305 [M + H] ⁺ , 3.36 minutes (retention time)

D87
4- (4-Chloro-3-fluorophenoxy) -3,5-difluorobenzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび４‐クロロ‐３‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ＋Ｈ］^＋、３．６４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 4-chloro-3-fluorophenol.
LC-MS (ESI): m / z 287 [M + H] ⁺ , 3.64 minutes (retention time)

D88
(4- (4-Chloro-3-fluorophenoxy) -3,5-difluorophenyl) methanol

表題の化合物を、４‐（４‐クロロ‐３‐フルオロフェノキシ）‐３，５‐ジフルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋Ｈ］^＋、３．３５分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (4-chloro-3-fluorophenoxy) -3,5-difluorobenzaldehyde.
LC-MS (ESI): m / z 289 [M + H] ⁺ , 3.35 minutes (retention time)

D89
4- (3-Chloro-4-fluorophenoxy) -3,5-difluorobenzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐クロロ‐４‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ＋Ｈ］^＋、３．６２分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chloro-4-fluorophenol.
LC-MS (ESI): m / z 287 [M + H] ⁺ , 3.62 minutes (retention time)

D90
(4- (3-Chloro-4-fluorophenoxy) -3,5-difluorophenyl) methanol

表題の化合物を、４‐（３‐クロロ‐４‐フルオロフェノキシ）‐３，５‐ジフルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋Ｈ］^＋、３．２９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-chloro-4-fluorophenoxy) -3,5-difluorobenzaldehyde.
LC-MS (ESI): m / z 289 [M + H] ⁺ , 3.29 minutes (retention time)

D91
2- (3-Chloro-4-fluorophenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび３‐クロロ‐４‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７６［Ｍ＋Ｈ］^＋、３．３１分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3-chloro-4-fluorophenol.
LC-MS (ESI): m / z 276 [M + H] ⁺ , 3.31 min (retention time)

D92
2- (3-Chloro-4-fluorophenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（３‐クロロ‐４‐フルオロフェノキシ）‐５‐ホルミルベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７８［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (3-chloro-4-fluorophenoxy) -5-formylbenzonitrile.
LC-MS (ESI): m / z 278 [M + H] ⁺ , 3.02 minutes (retention time)

D93
3- (2-Fluoro-4-formylphenoxy) benzonitrile

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐ヒドロキシベンゾニトリルから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４２［Ｍ＋Ｈ］^＋、３．０７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3-hydroxybenzonitrile.
LC-MS (ESI): m / z 242 [M + H] ⁺ , 3.07 minutes (retention time)

D94
3- (2-Fluoro-4- (hydroxymethyl) phenoxy) benzonitrile

表題の化合物を、３‐（２‐フルオロ‐４‐ホルミルフェノキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２２６［Ｍ−１７］^＋、２．７４分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3- (2-fluoro-4-formylphenoxy) benzonitrile.
LC-MS (ESI): m / z 226 [M-17] ⁺ , 2.74 minutes (retention time)

D95
5-Formyl-2- (pyrimidin-5-yloxy) benzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよびピリミジン‐５‐オールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２２６［Ｍ＋Ｈ］^＋、１．８７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and pyrimidin-5-ol.
LC-MS (ESI): m / z 226 [M + H] ⁺ , 1.87 minutes (retention time)

D96
5- (Hydroxymethyl) -2- (pyrimidin-5-yloxy) benzonitrile

表題の化合物を、５‐ホルミル‐２‐（ピリミジン‐５‐イルオキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２２８［Ｍ−１７］^＋、１．３８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 5-formyl-2- (pyrimidin-5-yloxy) benzonitrile.
LC-MS (ESI): m / z 228 [M-17] ⁺ , 1.38 minutes (retention time)

D97
3,5-Difluoro-4- (3-fluorophenoxy) benzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５３［Ｍ＋Ｈ］^＋、３．４４分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluorophenol.
LC-MS (ESI): m / z 253 [M + H] ⁺ , 3.44 minutes (retention time)

D98
(3,5-Difluoro-4- (3-fluorophenoxy) phenyl) methanol

表題の化合物を、３，５‐ジフルオロ‐４‐（３‐フルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５５［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3,5-difluoro-4- (3-fluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 255 [M + H] ⁺ , 3.02 minutes (retention time)

D99
3,5-Difluoro-4- (3-fluoro-4- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐フルオロ‐４‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２１［Ｍ＋Ｈ］^＋、３．７０分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluoro-4- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 321 [M + H] ⁺ , 3.70 minutes (retention time)

D100
(3,5-difluoro-4- (3-fluoro-4- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３，５‐ジフルオロ‐４‐（３‐フルオロ‐４‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２３［Ｍ＋Ｈ］^＋、３．４６分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3,5-difluoro-4- (3-fluoro-4- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 323 [M + H] ⁺ , 3.46 minutes (retention time)

D101
3,5-Difluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０５［Ｍ＋Ｈ］^＋、３．３６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 305 [M + H] ⁺ , 3.36 minutes (retention time)

D102
(3,5-Difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３，５‐ジフルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０５［Ｍ＋Ｈ］^＋、３．３６分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 305 [M + H] ⁺ , 3.36 minutes (retention time)

D103
4- (3-Chlorophenoxy) -3,5-difluorobenzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３‐クロロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６９［Ｍ＋Ｈ］^＋、３．６３分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chlorophenol.
LC-MS (ESI): m / z 269 [M + H] ⁺ , 3.63 minutes (retention time)

D104
(4- (3-Chlorophenoxy) -3,5-difluorophenyl) methanol

表題の化合物を、４‐（３‐クロロフェノキシ）‐３，５‐ジフルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７１［Ｍ＋Ｈ］^＋、３．２８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-chlorophenoxy) -3,5-difluorobenzaldehyde.
LC-MS (ESI): m / z 271 [M + H] ⁺ , 3.28 minutes (retention time)

D105
4- (3,4-Difluorophenoxy) -3,5-difluorobenzaldehyde

表題の化合物を、３，４，５‐トリフルオロベンズアルデヒドおよび３，４‐ジフルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７１［Ｍ＋Ｈ］^＋、３．４７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,4-difluorophenol.
LC-MS (ESI): m / z 271 [M + H] ⁺ , 3.47 minutes (retention time)

D106
(4- (3,4-Difluorophenoxy) -3,5-difluorophenyl) methanol

表題の化合物を、（４‐（３，４‐ジフルオロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７３［Ｍ＋Ｈ］^＋、３．１５分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from (4- (3,4-difluorophenoxy) -3,5-difluorophenyl) methanol.
LC-MS (ESI): m / z 273 [M + H] ⁺ , 3.15 minutes (retention time)

D107
4-((2-Chloropyridin-4-yl) oxy) -3-fluorobenzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび２‐クロロピリジン‐４‐オールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６９［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 2-chloropyridin-4-ol.
LC-MS (ESI): m / z 269 [M + H] ⁺ , 3.02 minutes (retention time)

D108
(4-((2-Chloropyridin-4-yl) oxy) -3-fluorophenyl) methanol

表題の化合物を、４４‐（（２‐クロロピリジン‐４‐イル）オキシ）‐３‐フルオロベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７１［Ｍ＋Ｈ］^＋、２．６７分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 44-((2-chloropyridin-4-yl) oxy) -3-fluorobenzaldehyde.
LC-MS (ESI): m / z 271 [M + H] ⁺ , 2.67 minutes (retention time)

D109
2- (4-Chloro-3-fluorophenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび４‐クロロ‐３‐フルオロフェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７６［Ｍ＋Ｈ］^＋、３．３３分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-fluorophenol.
LC-MS (ESI): m / z 276 [M + H] ⁺ , 3.33 minutes (retention time)

D110
2- (4-Chloro-3-fluorophenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（３‐クロロ‐４‐フルオロフェノキシ）‐５‐ホルミルベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７８［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (3-chloro-4-fluorophenoxy) -5-formylbenzonitrile.
LC-MS (ESI): m / z 278 [M + H] ⁺ , 3.02 minutes (retention time)

D111
4- (4-Chloro-3-trifluoromethyl-phenoxy) -3-fluoro-benzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび４‐クロロ‐３‐トリフルオロメチル‐フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１９［Ｍ＋Ｈ］^＋、１．２２分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 4-chloro-3-trifluoromethyl-phenol.
LC-MS (ESI): m / z 319 [M + H] ⁺ , 1.22 minutes (retention time)

D112
[4- (4-Chloro-3-trifluoromethyl-phenoxy) -3-fluoro-phenyl] methanol

表題の化合物を、４‐（４‐クロロ‐３‐トリフルオロメチル‐フェノキシ）‐３‐フルオロ‐ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０３［Ｍ＋Ｈ］^＋、１．１７分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (4-chloro-3-trifluoromethyl-phenoxy) -3-fluoro-benzaldehyde.
LC-MS (ESI): m / z 303 [M + H] ⁺ , 1.17 minutes (retention time)

D113
3-Fluoro-5- (2-fluoro-4-formyl-phenoxy) -benzonitrile

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐フルオロ‐５‐ヒドロキシベンゾニトリルから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６０［Ｍ＋Ｈ］^＋、１．０７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluoro-5-hydroxybenzonitrile.
LC-MS (ESI): m / z 260 [M + H] ⁺ , 1.07 minutes (retention time)

D114
3-Fluoro-5- (2-fluoro-4- (hydroxymethyl) phenoxy) benzonitrile

表題の化合物を、３‐フルオロ‐５‐（２‐フルオロ‐４‐ホルミル‐フェノキシ）‐ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４４［Ｍ＋Ｈ］^＋、０．９８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-5- (2-fluoro-4-formyl-phenoxy) -benzonitrile.
LC-MS (ESI): m / z 244 [M + H] ⁺ , 0.98 minutes (retention time)

D115
4- (4-Fluoro-3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、４‐フルオロベンズアルデヒドおよび４‐フルオロ‐３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ＋Ｈ］^＋、３．６１分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 4-fluorobenzaldehyde and 4-fluoro-3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 285 [M + H] ⁺ , 3.61 min (retention time)

D116
(4- (4-Fluoro-3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、４‐（４‐フルオロ‐３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ＋Ｈ］^＋、３．２８分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 287 [M + H] ⁺ , 3.28 minutes (retention time)

D117
3-Fluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロベンズアルデヒドおよび３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ＋Ｈ］^＋、３．４７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorobenzaldehyde and 3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 285 [M + H] ⁺ , 3.47 minutes (retention time)

D118
(3-Fluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol

表題の化合物を、３‐フルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８７［Ｍ＋Ｈ］^＋、３．２２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 3-fluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde.
LC-MS (ESI): m / z 287 [M + H] ⁺ , 3.22 minutes (retention time)

D119
Preparation of 2-fluoro-4- (2-hydroxy-ethyl) -phenol

ＴＨＦ（５００ｍＬ）中の２‐（３‐フルオロ‐４‐ヒドロキシフェニル）酢酸（９．８ｇ、５７．６ｍｍｏｌ）の溶液へ、５７．６ｍＬのボラン（Ｍｅ_２Ｓ中の１０Ｍ）を室温にて滴下した。この反応混合物を、室温にて１２時間攪拌した。この反応混合物を、ＣＨ_３ＯＨに添加し、減圧濃縮した。残渣を、ＥｔＯＡｃ（８００ｍＬ）と水（１００ｍＬ）とに分配した。有機層を乾燥し、濃縮乾固して、表題の生成物を得た（８．５ｇ、７６％）。
^１Ｈ ＮＭＲ（ＤＭＳＯ，４００ＭＨｚ）：δ ｐｐｍ ２．５９（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ，），３．５３（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ，），４．６０（ｂｓ，１Ｈ），６．８０‐６．８６（ｍ，２Ｈ），６．９６‐６．９９（ｍ，２Ｈ），９．５４（ｓ，１Ｈ）

To a solution of 2- (3-fluoro-4-hydroxyphenyl) acetic acid (9.8 g, 57.6 mmol) in THF (500 mL), 57.6 mL of borane (10 M in Me ₂ S) was added dropwise at room temperature. did. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was added to CH ₃ OH and concentrated under reduced pressure. The residue was partitioned between EtOAc (800 mL) and water (100 mL). The organic layer was dried and concentrated to dryness to give the title product (8.5 g, 76%).
¹ H NMR (DMSO, 400 MHz): δ ppm 2.59 (t, J = 7.2 Hz, 2H,), 3.53 (t, J = 7.2 Hz, 2H,), 4.60 (bs, 1H) ), 6.80-6.86 (m, 2H), 6.96-6.99 (m, 2H), 9.54 (s, 1H)

D120
2- [4- (4-Chloro-3-fluoro-phenoxy) -3-fluoro-phenyl] -ethanol

乾燥ＣＨ_２Ｃｌ_２（１５０ｍＬ）中の２‐フルオロ‐４‐（２‐ヒドロキシエチル）フェノール（２２．４１ｍｍｏｌ、３．５ｇ）および（４‐クロロ‐３‐フルオロフェニル）ボロン酸（４５ｍｍｏｌ、７．８２ｇ）の溶液へ、酢酸銅（ＩＩ）（４．５ｍｍｏｌ、０．８１ｇ）、ピリジン（４５ｍｍｏｌ、３．５５ｇ）、および４Ａ モレキュラーシーブを順に添加した。この混合物を、Ｎ_２下、室温にて７２時間攪拌した。この反応混合物をろ過し、ろ液を濃縮して、粗生成物を得た。この粗生成物を、シリカゲルクロマトグラフィで精製して、所望される生成物を得た（１．４ｇ、２０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ＋Ｈ］^＋、１．０９分（保持時間）

Dry _CH 2 _Cl 2 (150 mL) solution of 2-fluoro-4- (2-hydroxyethyl) phenol (22.41mmol, 3.5g) and (4-chloro-3-fluorophenyl) boronic acid (45 mmol, 7. To a solution of 82 g), copper (II) acetate (4.5 mmol, 0.81 g), pyridine (45 mmol, 3.55 g), and 4A molecular sieve were sequentially added. The mixture, _{N 2} was stirred under at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel chromatography to give the desired product (1.4 g, 20%).
LC-MS (ESI): m / z 285 [M + H] ⁺ , 1.09 minutes (retention time)

D121
2- [4- (3-Chloro-4-fluoro-phenoxy) -phenyl] -ethanol

表題の化合物を、４‐（２‐ヒドロキシエチル）フェノールおよび（３‐クロロ‐４‐フルオロフェニル）ボロン酸から出発して、Ｄ１２０についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２４９［Ｍ＋Ｈ］^＋、１．０８分（保持時間）

The title compound was made in a similar procedure as described for D120 starting from 4- (2-hydroxyethyl) phenol and (3-chloro-4-fluorophenyl) boronic acid.
LC-MS (ESI): m / z 249 [M + H] ⁺ , 1.08 minutes (retention time)

D122
4- (2-Cyano-4-formylphenoxy) -2-fluorobenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび２‐フルオロ‐４‐ヒドロキシベンゾニトリルから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６７［Ｍ＋Ｈ］^＋、２．９７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluoro-4-hydroxybenzonitrile.
LC-MS (ESI): m / z 267 [M + H] ⁺ , 2.97 minutes (retention time)

D123
4- (2-Cyano-4- (hydroxymethyl) phenoxy) -2-fluorobenzonitrile

表題の化合物を、４‐（２‐シアノ‐４‐ホルミルフェノキシ）‐２‐フルオロベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６９［Ｍ＋Ｈ］^＋、２．６５分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (2-cyano-4-formylphenoxy) -2-fluorobenzonitrile.
LC-MS (ESI): m / z 269 [M + H] ⁺ , 2.65 minutes (retention time)

D124
2- [3-Fluoro-4- (3-trifluoromethyl-phenoxy) -phenyl] -ethanol

表題の化合物を、２‐フルオロ‐４‐（２‐ヒドロキシエチル）フェノールおよび（３‐（トリフルオロメチル）フェニル）ボロン酸から出発して、Ｄ１２０についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０１［Ｍ＋Ｈ］^＋、１．１５分（保持時間）

The title compound was made in a similar procedure as described for D120 starting from 2-fluoro-4- (2-hydroxyethyl) phenol and (3- (trifluoromethyl) phenyl) boronic acid.
LC-MS (ESI): m / z 301 [M + H] ⁺ , 1.15 minutes (retention time)

D125
2-Chloro-4- (2-cyano-4-formylphenoxy) benzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび２‐クロロ‐４‐ヒドロキシベンゾニトリルから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８３［Ｍ＋Ｈ］^＋、３．０７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloro-4-hydroxybenzonitrile.
LC-MS (ESI): m / z 283 [M + H] ⁺ , 3.07 minutes (retention time)

D126
2-Chloro-4- (2-cyano-4- (hydroxymethyl) phenoxy) benzonitrile

表題の化合物を、２‐クロロ‐４‐（２‐シアノ‐４‐ホルミルフェノキシ）ベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８５［Ｍ＋Ｈ］^＋、２．７９分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2-chloro-4- (2-cyano-4-formylphenoxy) benzonitrile.
LC-MS (ESI): m / z 285 [M + H] ⁺ , 2.79 minutes (retention time)

D127
2- (4-Chloro-3- (trifluoromethyl) phenoxy) -5-formylbenzonitrile

表題の化合物を、２‐フルオロ‐５‐ホルミルベンゾニトリルおよび４‐クロロ‐３‐（トリフルオロメチル）フェノールから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２６［Ｍ＋Ｈ］^＋、３．５５分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3- (trifluoromethyl) phenol.
LC-MS (ESI): m / z 326 [M + H] ⁺ , 3.55 minutes (retention time)

D128
2- (4-Chloro-3- (trifluoromethyl) phenoxy) -5- (hydroxymethyl) benzonitrile

表題の化合物を、２‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）‐５‐ホルミルベンゾニトリルから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２８［Ｍ＋Ｈ］^＋、３．２７分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 2- (4-chloro-3- (trifluoromethyl) phenoxy) -5-formylbenzonitrile.
LC-MS (ESI): m / z 328 [M + H] ⁺ , 3.27 minutes (retention time)

D129
4- (3-Fluoro-4-methylphenoxy) benzaldehyde

表題の化合物を、３‐フルオロ‐４‐メチルフェノールおよび４‐フルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３１［Ｍ＋Ｈ］^＋、３．５７分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3-fluoro-4-methylphenol and 4-fluorobenzaldehyde.
LC-MS (ESI): m / z 231 [M + H] ⁺ , 3.57 minutes (retention time)

D130
(4- (3-Fluoro-4-methylphenoxy) phenyl) methanol

表題の化合物を、４‐（３‐フルオロ‐４‐メチルフェノキシ）ベンズアルデヒドから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２１５［Ｍ−１７］^＋、３．１６分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from 4- (3-fluoro-4-methylphenoxy) benzaldehyde.
LC-MS (ESI): m / z 215 [M-17] ⁺ , 3.16 minutes (retention time)

D131
Ethyl 2-chloro-6- (3,4-difluorophenoxy) -5-fluoronicotinate

アセトニトリル（２００ｍＬ）中のエチル２，６‐ジクロロ‐５‐フルオロニコチネート（２０ｇ、８４ｍｍｏｌ）および３，４‐ジフルオロフェノール（１０．９３ｇ、８４ｍｍｏｌ）の溶液へ、炭酸カリウム（２０．９０ｇ、１５１ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌し、続いて減圧濃縮した。粗生成物を、Ｈｅｘ／ＥｔＯＡｃ（１０：１）で溶出するシリカゲルクロマトグラフィで精製して、エチル２‐クロロ‐６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロニコチネートを得た（２３．５ｇ、８０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３２［Ｍ＋Ｈ］^＋、１．２４分（保持時間）

To a solution of ethyl 2,6-dichloro-5-fluoronicotinate (20 g, 84 mmol) and 3,4-difluorophenol (10.93 g, 84 mmol) in acetonitrile (200 mL), potassium carbonate (20.90 g, 151 mmol) Was added. The reaction mixture was stirred at 80 ° C. for 2 hours and subsequently concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex / EtOAc (10: 1) to give ethyl 2-chloro-6- (3,4-difluorophenoxy) -5-fluoronicotinate (23. 5g, 80%).
LC-MS (ESI): m / z 332 [M + H] ⁺ , 1.24 minutes (retention time)

D132
Ethyl 6- (3,4-difluorophenoxy) -5-fluoronicotinate

メタノール（３００ｍＬ）中のギ酸アンモニウム（２８．５ｇ、４５２ｍｍｏｌ）およびエチル２‐クロロ‐６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロニコチネート（３０ｇ、９０ｍｍｏｌ）の溶液へ、Ｐｄ／Ｃ（３ｇ、２．８２ｍｍｏｌ）を添加した。この反応混合物を、６５℃にて１０時間攪拌し、続いてろ過した。ろ液を減圧濃縮して、エチル６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロニコチネートを得た（２０ｇ、４８．４％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９８［Ｍ＋Ｈ］^＋、１．２２分（保持時間）

To a solution of ammonium formate (28.5 g, 452 mmol) and ethyl 2-chloro-6- (3,4-difluorophenoxy) -5-fluoronicotinate (30 g, 90 mmol) in methanol (300 mL), Pd / C ( 3 g, 2.82 mmol) was added. The reaction mixture was stirred at 65 ° C. for 10 hours and subsequently filtered. The filtrate was concentrated in vacuo to give ethyl 6- (3,4-difluorophenoxy) -5-fluoronicotinate (20 g, 48.4%).
LC-MS (ESI): m / z 298 [M + H] ⁺ , 1.22 minutes (retention time)

D133
(6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) methanol

表題の化合物を、エチル６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロニコチネートから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２５６［Ｍ＋Ｈ］^＋、１．０３分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from ethyl 6- (3,4-difluorophenoxy) -5-fluoronicotinate.
LC-MS (ESI): m / z 256 [M + H] ⁺ , 1.03 minutes (retention time)

D134
(6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) methylmethanesulfonate

ジクロロメタン（ＤＣＭ）（１００ｍＬ）中の（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）メタノール（８．４ｇ、２６．７ｍｍｏｌ）およびトリエチルアミン（６．８９ｍＬ、４９．４ｍｍｏｌ）の溶液へ、塩化メタンスルホニル（４．８ｇ、４１．９ｍｍｏｌ）を添加した。この反応混合物を２０℃にて２時間攪拌し、次に２００ｍＬのＨ_２Ｏを添加した。有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、続いて減圧濃縮して、（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）メチルメタンスルホネートを得た（８ｇ、４２．３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３４［Ｍ＋Ｈ］^＋、１．１３分（保持時間）

(6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) methanol (8.4 g, 26.7 mmol) and triethylamine (6.89 mL, 49.4 mmol) in dichloromethane (DCM) (100 mL) ) Was added methanesulfonyl chloride (4.8 g, 41.9 mmol). The reaction mixture was stirred at 20 ° C. for 2 hours and then 200 mL of H ₂ O was added. The organic layer was separated, dried over Na ₂ SO ₄ and subsequently concentrated in vacuo to give (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) methyl methanesulfonate ( 8g, 42.3%).
LC-MS (ESI): m / z 334 [M + H] ⁺ , 1.13 minutes (retention time)

D135
2- (6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) acetonitrile

アセトニトリル（１００ｍＬ）中の（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）メチルメタンスルホネート（８ｇ、１１．２８ｍｍｏｌ）およびフッ化テトラブチルアンモニウム（５．９０ｇ、２２．５６ｍｍｏｌ）の溶液へ、シアン化トリメチルシリル（３．０２ｍＬ、２２．５６ｍｍｏｌ）を添加した。この反応混合物を８０℃にて２時間攪拌し、次に減圧濃縮した。この粗生成物を、Ｈｅｘ／ＥｔＯＡｃ（５：１）で溶出するシリカゲルクロマトグラフィで精製して、２‐（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）アセトニトリルを得た（３ｇ、８９％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２６５［Ｍ＋Ｈ］^＋、１．０９分（保持時間）

(6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) methyl methanesulfonate (8 g, 11.28 mmol) and tetrabutylammonium fluoride (5.90 g, 22.25 mg) in acetonitrile (100 mL). To a solution of 56 mmol) trimethylsilyl cyanide (3.02 mL, 22.56 mmol) was added. The reaction mixture was stirred at 80 ° C. for 2 hours and then concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with Hex / EtOAc (5: 1) to give 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) acetonitrile. (3 g, 89%).
LC-MS (ESI): m / z 265 [M + H] ⁺ , 1.09 minutes (retention time)

D136
Ethyl 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) acetate

２‐（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）アセトニトリル（３ｇ、９．９９ｍｍｏｌ）およびＥｔＯＨ（３０ｍＬ、５１４ｍｍｏｌ）へ、１８Ｍ 硫酸（１０ｍＬ、１８０ｍｍｏｌ）を添加した。この反応混合物を、８０℃にて２時間攪拌し、次に減圧濃縮した。残渣へ、５０ｍＬの濃アンモニア溶液および１００ｍＬのＣＨ_２Ｃｌ_２を添加した。有機層を分離し、Ｎａ_２ＳＯ_４上で乾燥し、続いて減圧濃縮して、エチル２‐（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）アセテートを得た（３．１ｇ、６７．８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１２［Ｍ＋Ｈ］^＋、１．１７分（保持時間）

To 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) acetonitrile (3 g, 9.99 mmol) and EtOH (30 mL, 514 mmol) was added 18M sulfuric acid (10 mL, 180 mmol). . The reaction mixture was stirred at 80 ° C. for 2 hours and then concentrated under reduced pressure. To the residue was added 50 mL concentrated ammonia solution and 100 mL CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ and subsequently concentrated in vacuo to give ethyl 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) acetate. (3.1 g, 67.8%).
LC-MS (ESI): m / z 312 [M + H] ⁺ , 1.17 minutes (retention time)

D137
2- (6- (3,4-Difluorophenoxy) -5-fluoropyridin-3-yl) ethanol

表題の化合物を、エチル２‐（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）アセテートから出発して、Ｄ５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２７０［Ｍ＋Ｈ］^＋、１．０２分（保持時間）

The title compound was made in a similar procedure as described for D5 starting from ethyl 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) acetate.
LC-MS (ESI): m / z 270 [M + H] ⁺ , 1.02 minutes (retention time)

D138
4- (3,4-Difluorophenoxy) benzaldehyde

表題の化合物を、３，４‐ジフルオロフェノールおよび４‐フルオロベンズアルデヒドから出発して、Ｄ４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３５［Ｍ＋Ｈ］^＋、３．３６分（保持時間）

The title compound was made in a similar procedure as described for D4 starting from 3,4-difluorophenol and 4-fluorobenzaldehyde.
LC-MS (ESI): m / z 235 [M + H] ⁺ , 3.36 minutes (retention time)

D139
1,2-difluoro-4- (4-vinylphenoxy) benzene

表題の化合物を、４‐（３，４‐ジフルオロフェノキシ）ベンズアルデヒドから出発して、Ｄ６４についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３３［Ｍ＋Ｈ］^＋、３．９９分（保持時間）

The title compound was made in a similar procedure as described for D64 starting from 4- (3,4-difluorophenoxy) benzaldehyde.
LC-MS (ESI): m / z 233 [M + H] ⁺ , 3.99 minutes (retention time)

D140
2- (4- (3,4-Difluorophenoxy) phenyl) ethanol

表題の化合物を、１，２‐ジフルオロ‐４‐（４‐ビニルフェノキシ）ベンゼンから出発して、Ｄ６５についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２３４［Ｍ＋Ｈ］^＋、３．１４分（保持時間）

The title compound was made in a similar procedure as described for D65 starting from 1,2-difluoro-4- (4-vinylphenoxy) benzene.
LC-MS (ESI): m / z 234 [M + H] ⁺ , 3.14 minutes (retention time)

D141
N- (3-Bromopropyl) -2,6-dichloropyrimidin-4-amine

アセトニトリル（２０００ｍＬ）中の２，４，６‐トリクロロピリミジン（１００ｇ、５４５ｍｍｏｌ）の溶液に、トリエチルアミン（１６６ｇ、１６３６ｍｍｏｌ）を０℃にて添加した。この反応混合物を、室温にて５分間攪拌し、続いて、３‐ブロモプロパン‐１‐アミン臭化水素酸塩（１１９ｇ、５４５ｍｍｏｌ）を少しずつ添加した。この反応混合物を、室温にて１時間攪拌し、ろ過して、透明溶液を得た。ＦＣで精製することにより、表題の化合物を白色固体として得た（４７ｇ、収率３０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８６［Ｍ＋Ｈ］^＋、１．１３分（保持時間）

To a solution of 2,4,6-trichloropyrimidine (100 g, 545 mmol) in acetonitrile (2000 mL), triethylamine (166 g, 1636 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of 3-bromopropan-1-amine hydrobromide (119 g, 545 mmol) in small portions. The reaction mixture was stirred at room temperature for 1 hour and filtered to give a clear solution. Purification by FC gave the title compound as a white solid (47 g, 30% yield).
LC-MS (ESI): m / z 286 [M + H] ⁺ , 1.13 minutes (retention time)

D142
8-Chloro-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

１，４‐ジオキサン（１００ｍＬ）および水（１００ｍＬ）中のＮ‐（３‐ブロモプロピル）‐２，６‐ジクロロピリミジン‐４‐アミン（４７ｇ、１６５ｍｍｏｌ）および炭酸カリウム（６８．４ｇ、４９５ｍｍｏｌ）の懸濁液を、一晩６０℃に加熱した。この混合物を蒸発させてジオキサン溶媒を除去し、混合物をＨＣｌ（６Ｍ）により約ｐＨ６に調節した。この混合物を、酢酸エチルで抽出して副生物を除去し、水相をＮａＯＨ（２Ｍ）により約ｐＨ７に調節し、蒸発させて、表題の化合物を得た（１７ｇ、収率５５％）。

Of N- (3-bromopropyl) -2,6-dichloropyrimidin-4-amine (47 g, 165 mmol) and potassium carbonate (68.4 g, 495 mmol) in 1,4-dioxane (100 mL) and water (100 mL). The suspension was heated to 60 ° C. overnight. The mixture was evaporated to remove the dioxane solvent and the mixture was adjusted to about pH 6 with HCl (6M). The mixture was extracted with ethyl acetate to remove by-products and the aqueous phase was adjusted to about pH 7 with NaOH (2M) and evaporated to give the title compound (17 g, 55% yield).

D143
tert-Butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine-1-carboxylate

テトラヒドロフラン（ＴＨＦ）（１００ｍＬ）中の粗８‐クロロ‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（８．０ｇ、４３．１ｍｍｏｌ）の溶液へ、（Ｂｏｃ）_２Ｏ（２０．０１ｍＬ、８６ｍｍｏｌ）およびＤＭＡＰ（０．５２７ｇ、４．３１ｍｍｏｌ）を添加した。この反応混合物を、室温にて２時間攪拌し、ＥＡと水とに分配した。有機層を水で洗浄し、（Ｎａ_２ＳＯ_４）上で乾燥し、蒸発させて、表題の化合物を得た（１２ｇ、収率９７％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８６［Ｍ＋１］＋、０．９８（保持時間）

To a solution of crude 8-chloro-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (8.0 g, 43.1 mmol) in tetrahydrofuran (THF) (100 mL) , (Boc) ₂ O (20.01 mL, 86 mmol) and DMAP (0.527 g, 4.31 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and partitioned between EA and water. The organic layer was washed with water, dried over (Na ₂ SO ₄ ) and evaporated to give the title compound (12 g, 97% yield).
LC-MS (ESI): m / z 286 [M + 1] +, 0.98 (retention time)

Example
E1: 5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (3 -(Trifluoromethyl) phenoxy) benzonitrile

Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（１．５ｍＬ）中の８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（３１ｍｇ、０．１５３ｍｍｏｌ）および５‐（ヒドロキシメチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリル（４９．４ｍｇ、０．１６８ｍｍｏｌ）の溶液へ、ＮａＨ（１８．３６ｍｇ、０．４５９ｍｍｏｌ）を添加した。この反応混合物を、室温にて３０分間攪拌した。ＨＣｌ水溶液を添加して、ｐＨを約７に調節した。質量分析付き自動分取（ＭＤＡＰ）で精製して、表題の化合物を白色固体として得た（３５ｍｇ、収率５０％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５７［Ｍ＋Ｈ］^＋、２．７２分（保持時間）

8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (31 mg) in N, N-dimethylformamide (DMF) (1.5 mL) , 0.153 mmol) and 5- (hydroxymethyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile (49.4 mg, 0.168 mmol) into a solution of NaH (18.36 mg, 0.459 mmol). Was added. The reaction mixture was stirred at room temperature for 30 minutes. Aqueous HCl was added to adjust the pH to about 7. Purification by automatic fractionation with mass spectrometry (MDAP) gave the title compound as a white solid (35 mg, 50% yield).
LC-MS (ESI): m / z 457 [M + H] ⁺ , 2.72 minutes (retention time)

E2: 5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2-(( 5- (Trifluoromethyl) pyridin-2-yl) oxy) benzonitrile

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび５‐（ヒドロキシメチル）‐２‐（（５‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）ベンゾニトリルから出発して、Ｅ１についての記載に類似の手順で作製した。代表的なプロセスを以下に示す： Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（５ｍＬ）中の５‐（ヒドロキシメチル）‐２‐（（５‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）ベンゾニトリル（０．１０８ｍＬ、０．６０１ｍｍｏｌ）の溶液へ、ＮａＨ（４８．１ｍｇ、１．２０２ｍｍｏｌ）を添加し、１０分間攪拌した。次に、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（８０ｍｇ、０．４０１ｍｍｏｌ）を投入し、室温にて４５分間攪拌した。得られた溶液を、１ｍＬのＮＨ_４Ｃｌ水溶液を添加することで反応停止し、この溶液をろ過した。得られた溶液をＭＤＡＰに掛けて、所望される生成物を白色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５８［Ｍ＋Ｈ］^＋、２．５５分（保持時間）

The title compound was converted to 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and 5- (hydroxymethyl) -2-((5 Prepared in a similar procedure as described for E1, starting from-(trifluoromethyl) pyridin-2-yl) oxy) benzonitrile. A representative process is shown below: 5- (Hydroxymethyl) -2-((5- (trifluoromethyl) pyridin-2-yl) oxy) benzo in N, N-dimethylformamide (DMF) (5 mL) To a solution of nitrile (0.108 mL, 0.601 mmol), NaH (48.1 mg, 1.202 mmol) was added and stirred for 10 minutes. Next, 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (80 mg, 0.401 mmol) was added, and 45 Stir for minutes. The resulting solution was quenched by adding 1 mL of NH ₄ Cl aqueous solution, and the solution was filtered. The resulting solution was subjected to MDAP to give the desired product as a white solid.
LC-MS (ESI): m / z 458 [M + H] ⁺ , 2.55 minutes (retention time)

E3: 8-((3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [ 1,6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（３，５‐ジフルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。代表的なプロセスを以下に示す： Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（１．５ｍＬ）中の８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン，トリフルオロ酢酸塩（４３ｍｇ、０．１３７ｍｍｏｌ）および（３，５‐ジフルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）フェニル）メタノール（４６．０ｍｇ、０．１５１ｍｍｏｌ）の溶液へ、ＮａＨ（１６．４５ｍｇ，０．４１１ｍｍｏｌ）を添加した。この混合物を、室温にて３０分間攪拌した。充分な量のＨＣｌ水溶液（１Ｍ）を添加して、溶液のｐＨを約７に調節した。得られた混合物を、質量分析付き自動分取（塩基性移動相）で精製して、表題の化合物を白色固体として得た（１８ｍｇ、０．０３８ｍｍｏｌ、収率２８．０％）。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ８．５０（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２７‐７．３０（ｍ，１Ｈ），７．１２（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），５．４０（ｓ，２Ｈ），５．１０（ｓ，１Ｈ），３．９９（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．４２（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），３．０１（ｓ，３Ｈ），２．０９（ｍ，Ｊ＝６．０Ｈｚ，２Ｈ）
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６９［Ｍ＋Ｈ］^＋、２．６５分（保持時間）

The title compound was converted to 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (3,5-difluoro-4-((6 Prepared in a similar procedure as described for E1, starting from-(trifluoromethyl) pyridin-3-yl) oxy) phenyl) methanol. A representative process is shown below: 8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine in N, N-dimethylformamide (DMF) (1.5 mL) -6 (2H) -one, trifluoroacetate (43 mg, 0.137 mmol) and (3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) methanol ( To a solution of 46.0 mg, 0.151 mmol) was added NaH (16.45 mg, 0.411 mmol). The mixture was stirred at room temperature for 30 minutes. A sufficient amount of aqueous HCl (1M) was added to adjust the pH of the solution to about 7. The resulting mixture was purified by automated preparative mass spectrometry (basic mobile phase) to give the title compound as a white solid (18 mg, 0.038 mmol, 28.0% yield).
¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.50 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.27-7.30 (m , 1H), 7.12 (d, J = 8.2 Hz, 2H), 5.40 (s, 2H), 5.10 (s, 1H), 3.99 (t, J = 5.9 Hz, 2H) ), 3.42 (t, J = 6.0 Hz, 2H), 3.01 (s, 3H), 2.09 (m, J = 6.0 Hz, 2H)
LC-MS (ESI): m / z 469 [M + H] ⁺ , 2.65 minutes (retention time)

E4: 8-((3-Fluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（３‐フルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５１［Ｍ＋Ｈ］^＋、２．５３分（保持時間）

The title compound was prepared from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (3-fluoro-4-((6- ( Prepared in a similar procedure as described for E1, starting from trifluoromethyl) pyridin-3-yl) oxy) phenyl) methanol.
LC-MS (ESI): m / z 451 [M + H] ⁺ , 2.53 minutes (retention time)

E5: 8-((4- (3,4-difluorophenoxy) -3-fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（４‐（３，４‐ジフルオロフェノキシ）‐３‐フルオロフェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１８［Ｍ＋Ｈ］^＋、２．６８分（保持時間）

The title compound is converted to 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (4- (3,4-difluorophenoxy)- Prepared in a similar procedure as described for E1, starting from 3-fluorophenyl) methanol.
LC-MS (ESI): m / z 418 [M + H] ⁺ , 2.68 minutes (retention time)

E6: 8-((4- (4-Chloro-3- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６６［Ｍ＋Ｈ］^＋、３．０２分（保持時間）

The title compound was prepared from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (4- (4-chloro-3- (tri Prepared in a similar procedure as described for E1, starting from fluoromethyl) phenoxy) phenyl) methanol.
LC-MS (ESI): m / z 466 [M + H] ⁺ , 3.02 minutes (retention time)

E7: 8-((4- (3,4-Dichlorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（４‐（３，４‐ジクロロフェノキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３２［Ｍ＋Ｈ］^＋、２．９６分（保持時間）

The title compound was converted to 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (4- (3,4-dichlorophenoxy) phenyl ) Made in a similar procedure as described for E1, starting from methanol.
LC-MS (ESI): m / z 432 [M + H] ⁺ , 2.96 minutes (retention time)

E8: 8-((4-Fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（４‐フルオロフェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９０［Ｍ＋Ｈ］^＋、１．８７分（保持時間）

The title compound is started from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (4-fluorophenyl) methanol. Produced in a similar procedure as described for E1.
LC-MS (ESI): m / z 290 [M + H] ⁺ , 1.87 minutes (retention time)

E9: 8-((4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenethyl) amino) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -one, trifluoroacetate

マイクロ波反応管へ、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（３１ｍｇ、０．１５３ｍｍｏｌ）、２‐（４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）エタナミン（０．０５８ｍＬ、０．１９１ｍｍｏｌ）、ＴＥＡ（０．０８５ｍＬ、０．６１２ｍｍｏｌ）、およびＮ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（１．５ｍＬ）を添加した。この反応混合物を、マイクロ波照射下、１４０℃にて３時間加熱した。次に、ＴＦＡを添加してｐＨを約５に調節した。質量分析付き自動分取（ＭＤＡＰ）で精製して、表題の化合物を白色固体として得た（６ｍｇ、収率６％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４７９［Ｍ＋Ｈ］^＋、３．１７分（保持時間）

To a microwave reaction tube, add 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (31 mg, 0.153 mmol), 2- (4 -(4-Chloro-3- (trifluoromethyl) phenoxy) phenyl) ethanamine (0.058 mL, 0.191 mmol), TEA (0.085 mL, 0.612 mmol), and N, N-dimethylformamide (DMF) ( 1.5 mL) was added. The reaction mixture was heated at 140 ° C. for 3 hours under microwave irradiation. Next, TFA was added to adjust the pH to about 5. Purification by automatic fractionation with mass spectrometry (MDAP) gave the title compound as a white solid (6 mg, 6% yield).
LC-MS (ESI): m / z 479 [M + H] ⁺ , 3.17 minutes (retention time)

E10: 8-((3,4-Difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one, trifluoroacetate

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（３，４‐ジフルオロフェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。代表的なプロセスを以下に示す： Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（５ｍＬ）中の（３，４‐ジフルオロフェニル）メタノール（０．０７９ｍＬ、０．９０２ｍｍｏｌ）の溶液へ、ＮａＨ（３６．１ｍｇ、０．９０２ｍｍｏｌ）を添加し、１０分間攪拌した。８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（６０ｍｇ、０．３０１ｍｍｏｌ）を添加し、室温にて４５分間攪拌した。次に、得られた溶液を、１ｍＬのＮＨ_４Ｃｌ水溶液を添加することで反応停止し、続いてろ過した。得られた溶液をＭＤＡＰで精製して、表題の化合物を白色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋Ｈ］^＋、１．９９分（保持時間）

The title compound is started from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (3,4-difluorophenyl) methanol. And was prepared by a procedure similar to that described for E1. A representative process is shown below: To a solution of (3,4-difluorophenyl) methanol (0.079 mL, 0.902 mmol) in N, N-dimethylformamide (DMF) (5 mL), NaH (36.1 mg). , 0.902 mmol) was added and stirred for 10 minutes. 8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (60 mg, 0.301 mmol) was added and stirred for 45 minutes at room temperature. . The resulting solution was then quenched by adding 1 mL of aqueous NH ₄ Cl and subsequently filtered. The resulting solution was purified with MDAP to give the title compound as a white solid.
LC-MS (ESI): m / z 308 [M + H] ⁺ , 1.99 minutes (retention time)

E11: 8- (4-Fluorophenoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one, trifluoroacetate

ＤＭＦ（４ｍＬ）中の２‐（４‐フルオロフェニル）エタノール（０．０７７ｍＬ、０．９０２ｍｍｏｌ）の溶液へ、カリウムｔｅｒｔ‐ブトキシド（１０１ｍｇ、０．９０２ｍｍｏｌ）を添加した。次に、この反応混合物を室温にて１０分間攪拌した。８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（６０ｍｇ、０．３０１ｍｍｏｌ）を投入し、室温にて１時間攪拌した。得られた溶液を、１ｍＬのＮＨ_４Ｃｌ水溶液を添加することで反応停止し、次にろ過した。質量分析付き自動分取（ＭＤＡＰ）で精製して、表題の化合物を淡黄色固体として得た（４２ｍｇ、３３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋Ｈ］^＋、２．０４分（保持時間）

To a solution of 2- (4-fluorophenyl) ethanol (0.077 mL, 0.902 mmol) in DMF (4 mL) was added potassium tert-butoxide (101 mg, 0.902 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. 8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (60 mg, 0.301 mmol) was added and stirred at room temperature for 1 hour. . The resulting solution was quenched by adding 1 mL of aqueous NH ₄ Cl and then filtered. Purification by automated fractionation with mass spectrometry (MDAP) gave the title compound as a pale yellow solid (42 mg, 33%).
LC-MS (ESI): m / z 308 [M + H] ⁺ , 2.04 minutes (retention time)

E12: 8-((2,3-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（２，３‐ジフルオロフェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋Ｈ］^＋、１．９１分（保持時間）

The title compound is started from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (2,3-difluorophenyl) methanol. And was prepared by a procedure similar to that described for E1.
LC-MS (ESI): m / z 308 [M + H] ⁺ , 1.91 minutes (retention time)

E13: 8-((3-Fluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Pyrimidine-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（３‐フルオロ‐４‐（４‐フルオロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６８［Ｍ＋Ｈ］^＋、２．８６分（保持時間）

The title compound was prepared from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (3-fluoro-4- (4-fluoro- Prepared in a similar procedure as described for E1, starting from 3- (trifluoromethyl) phenoxy) phenyl) methanol.
LC-MS (ESI): m / z 468 [M + H] ⁺ , 2.86 minutes (retention time)

E14: 8-((4- (3,4-Difluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物を、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンおよび（４‐（３，４‐ジフルオロフェノキシ）フェニル）メタノールから出発して、Ｅ１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４００［Ｍ＋Ｈ］^＋、２．５０分（保持時間）

The title compound was converted to 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one and (4- (3,4-difluorophenoxy) phenyl ) Made in a similar procedure as described for E1, starting from methanol.
LC-MS (ESI): m / z 400 [M + H] ⁺ , 2.50 minutes (retention time)

E15
8-((4- (3-Chloro-4-fluorophenoxy) -3-fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物またはその塩を、（４‐（３‐クロロ‐４‐フルオロフェノキシ）‐３‐フルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３４［Ｍ＋１］^＋、２．７２分（保持時間）

The title compound or a salt thereof is converted to (4- (3-chloro-4-fluorophenoxy) -3-fluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6 -A] Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 434 [M + 1] ⁺ , 2.72 minutes (retention time)

E16
8-((4- (3-Chlorophenoxy) -3-fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３‐クロロ‐４‐フルオロフェノキシ）‐３‐フルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１６［Ｍ＋１］^＋、２．７３分（保持時間）

The title compound or a salt thereof is converted to (4- (3-chloro-4-fluorophenoxy) -3-fluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6 -A] Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 416 [M + 1] ⁺ , 2.73 minutes (retention time)

E17
8-((4- (3-Chloro-4-fluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３‐クロロ‐４‐フルオロフェノキシ）フェニル）メタノール、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１６［Ｍ＋１］^＋、２．６９分（保持時間）

The title compound or salt thereof is converted to (4- (3-chloro-4-fluorophenoxy) phenyl) methanol, 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine Prepared in a similar procedure as described for E2, starting from -6 (2H) -one.
LC-MS (ESI): m / z 416 [M + 1] ⁺ , 2.69 minutes (retention time)

E18
8-((4-Chloro-3- (trifluoromethyl) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐クロロ‐３‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３７４［Ｍ＋１］^＋、２．４３分（保持時間）

The title compound or a salt thereof is converted to (4-chloro-3- (trifluoromethyl) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine- Prepared in a similar procedure as described for E2, starting from 6 (2H) -one.
LC-MS (ESI): m / z 374 [M + 1] ⁺ , 2.43 minutes (retention time)

E19
1-Methyl-8-((3- (trifluoromethyl) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３４０［Ｍ＋１］^＋、２．３０分（保持時間）

The title compound or salt thereof is converted to (3- (trifluoromethyl) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -Made from a procedure similar to that described for E2, starting from ON.
LC-MS (ESI): m / z 340 [M + 1] ⁺ , 2.30 minutes (retention time)

E20
8-((2,4-Difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（２，４‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋１］^＋、１．９４分（保持時間）

The title compound or a salt thereof is converted to (2,4-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one. Starting from, the procedure was similar to that described for E2.
LC-MS (ESI): m / z 308 [M + 1] ⁺ , 1.94 minutes (retention time)

E21
1-Methyl-8-((3,4,5-trifluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

ＤＭＦ（２ｍＬ）中のＮａＨ（３８．３ｍｇ、０．９５６ｍｍｏｌ）の溶液へ、（３，４，５‐トリフルオロフェニル）メタノール（６５ｍｇ、０．４０１ｍｍｏｌ）を室温にて添加した。この反応混合物を、室温にて５分間攪拌し、次に、８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン トリオフルオロ酢酸塩（１００ｍｇ、０．３１９ｍｍｏｌ）を添加した。この反応混合物を、室温にてさらに１時間攪拌し、水で反応停止し、次にろ過して、透明溶液を得た。この溶液を、ＭＤＡＰ（０．３％ ＴＦＡ含有水／ＭｅＣＮ）で精製して、表題の化合物をそのＴＦＡ塩として得た（１６ｍｇ、０．０３６ｍｍｏｌ、１１．４２％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２６［Ｍ＋１］^＋、２．１３分（保持時間）

To a solution of NaH (38.3 mg, 0.956 mmol) in DMF (2 mL), (3,4,5-trifluorophenyl) methanol (65 mg, 0.401 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -on trifluoro. Acetate (100 mg, 0.319 mmol) was added. The reaction mixture was stirred at room temperature for an additional hour, quenched with water and then filtered to give a clear solution. The solution was purified with MDAP (water containing 0.3% TFA / MeCN) to give the title compound as its TFA salt (16 mg, 0.036 mmol, 11.42%).
LC-MS (ESI): m / z 326 [M + 1] ⁺ , 2.13 minutes (retention time)

E22
8-((3-Fluoro-4- (trifluoromethyl) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３５８［Ｍ＋１］^＋、２．３７分（保持時間）

The title compound or a salt thereof is converted to (3-fluoro-4- (trifluoromethyl) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine- Prepared in a similar procedure as described for E2, starting from 6 (2H) -one.
LC-MS (ESI): m / z 358 [M + 1] ⁺ , 2.37 minutes (retention time)

E23
1-methyl-8-((4- (trifluoromethyl) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３４０［Ｍ＋１］^＋、２．３１分（保持時間）

The title compound or salt thereof is converted to (4- (trifluoromethyl) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -Made from a procedure similar to that described for E2, starting from ON.
LC-MS (ESI): m / z 340 [M + 1] ⁺ , 2.31 minutes (retention time)

E24
8-((4-Fluoro-3- (trifluoromethyl) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐フルオロ‐３‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３５８［Ｍ＋１］^＋、２．３５分（保持時間）

The title compound or salt thereof is converted to (4-fluoro-3- (trifluoromethyl) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine- Prepared in a similar procedure as described for E2, starting from 6 (2H) -one.
LC-MS (ESI): m / z 358 [M + 1] ⁺ , 2.35 minutes (retention time)

E25
8-((3-Fluoro-4- (3-fluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（３‐フルオロフェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４００［Ｍ＋Ｈ］^＋、２．６１分（保持時間）

The title compound or salt thereof is converted to (3-fluoro-4- (3-fluorophenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine Prepared in a similar procedure as described for E2, starting from -6 (2H) -one.
LC-MS (ESI): m / z 400 [M + H] ⁺ , 2.61 minutes (retention time)

E26
1-Methyl-8-((4-phenoxybenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐フェノキシフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３６４［Ｍ＋１］^＋、２．５８分（保持時間）

Starting from the title compound or its salt from (4-phenoxyphenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared in a similar procedure as described for E2.
LC-MS (ESI): m / z 364 [M + 1] ⁺ , 2.58 minutes (retention time)

E27
3-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) benzonitrile

表題の化合物またはその塩を、３‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９７［Ｍ＋１］^＋、１．７６分（保持時間）

The title compound or salt thereof from 3- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting and made in a similar procedure as described for E2.
LC-MS (ESI): m / z 297 [M + 1] ⁺ , 1.76 minutes (retention time)

E28
8-((3-Fluoro-4- (3- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物またはその塩を、（３‐フルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５０［Ｍ＋１］^＋、２．９１（保持時間）

The title compound or a salt thereof is converted to (3-fluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6 -A] Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 450 [M + 1] ⁺ , 2.91 (retention time)

E29
5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (4- ( Trifluoromethyl) phenoxy) benzonitrile

表題の化合物またはその塩を、５‐（ヒドロキシメチル）‐２‐（４‐（トリフルオロメチル）フェノキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５７［Ｍ＋１］^＋、２．８２（保持時間）

The title compound or salt thereof is converted to 5- (hydroxymethyl) -2- (4- (trifluoromethyl) phenoxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] Pyrimidin-6 (2H) -one was made in a similar procedure as described for E2 starting from 6
LC-MS (ESI): m / z 457 [M + 1] ⁺ , 2.82 (retention time)

E30
2- (4-Fluorophenoxy) -5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) Methyl) benzonitrile

表題の化合物またはその塩を、２‐（４‐フルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０７［Ｍ＋１］^＋、２．５２（保持時間）

The title compound or salt thereof is converted to 2- (4-fluorophenoxy) -5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a]. Made in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 407 [M + 1] ⁺ , 2.52 (retention time)

E31
8-((3,5-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３，５‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋１］^＋、１．９７（保持時間）

The title compound or a salt thereof is converted to (3,5-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting from, the procedure was similar to that described for E2.
LC-MS (ESI): m / z 308 [M + 1] ⁺ , 1.97 (retention time)

E32
8-((3-Fluoro-4-((6- (trifluoromethyl) pyridin-2-yl) oxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6- a] Pyrimidine-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５１［Ｍ＋Ｈ］^＋、２．６５分（保持時間）

The title compound or salt thereof is converted to (3-fluoro-4-((6- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro- Prepared in a similar procedure as described for E2 starting from 1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 451 [M + H] ⁺ , 2.65 minutes (retention time)

E33
3-Fluoro-5-(((1-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) benzonitrile

表題の化合物またはその塩を、３‐フルオロ‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１５［Ｍ＋１］^＋、１．８７（保持時間）

The title compound or a salt thereof was converted to 3-fluoro-5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H Prepared in a similar procedure as described for E2, starting from) -one.
LC-MS (ESI): m / z 315 [M + 1] ⁺ , 1.87 (retention time)

E34
2- (3,4-Difluorophenoxy) -5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) Oxy) methyl) benzonitrile

表題の化合物またはその塩を、２‐（３，４‐ジフルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４２５［Ｍ＋１］^＋、２．５９（保持時間）

The title compound or a salt thereof is converted to 2- (3,4-difluorophenoxy) -5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6- a] Made in a similar procedure as described for E2 starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 425 [M + 1] ⁺ , 2.59 (retention time)

E35
1-Methyl-8-((2,4,5-trifluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（２，４，５‐トリフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２６［Ｍ＋１］^＋、２．０２（保持時間）

The title compound or a salt thereof is converted to (2,4,5-trifluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H Prepared in a similar procedure as described for E2, starting from) -one.
LC-MS (ESI): m / z 326 [M + 1] ⁺ , 2.02 (retention time)

E36
8- [2- (4-Methoxy-phenyl) -ethoxy] -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

ジメチルスルホキシド（ＤＭＳＯ）（５ｍＬ）中の２‐（４‐メトキシフェニル）エタノール（１８３ｍｇ、１．２０２ｍｍｏｌ）および８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（２００ｍｇ、１．００２ｍｍｏｌ）の室温での攪拌溶液へ、ＮａＨ（１００ｍｇ、２．５０５ｍｍｏｌ）を少しずつ添加した。この反応混合物を、室温にて２時間攪拌した。水で反応停止し、分取用ＨＰＬＣで精製して、表題の生成物を白色固体として得た（１５０ｍｇ）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１６［Ｍ＋Ｈ］＋、０．７２分（保持時間）

2- (4-Methoxyphenyl) ethanol (183 mg, 1.202 mmol) and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a in dimethyl sulfoxide (DMSO) (5 mL) To a stirred solution of pyrimidin-6 (2H) -one (200 mg, 1.002 mmol) at room temperature, NaH (100 mg, 2.505 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and purified by preparative HPLC to give the title product as a white solid (150 mg).
LC-MS (ESI): m / z 316 [M + H] +, 0.72 minutes (retention time)

E37
8-((3-Fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９０［Ｍ＋１］^＋、１．８９（保持時間）

Starting from the title compound or its salt from (3-fluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared in a similar procedure as described for E2.
LC-MS (ESI): m / z 290 [M + 1] ⁺ , 1.89 (retention time)

E38
8-((3-Fluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) oxy) -1-isopropyl-3,4-dihydro-1H-pyrimido [1,6- a] Pyrimidine-6 (2H) -one

Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（８ｍＬ）中の（３‐フルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）フェニル）メタノール（１２６ｍｇ、０．４３９ｍｍｏｌ）および８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（２０ｍｇ、０．０８８ｍｍｏｌ）の溶液へ、ＮａＨ（３５．１ｍｇ、０．８７８ｍｍｏｌ）を添加し、室温にて１時間攪拌した。この反応混合物を、飽和ＮＨ_４Ｃｌ水溶液を添加することで反応停止し、ろ過した。この溶液を、ＭＤＡＰで精製して、所望される生成物を白色固体として得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４７９［Ｍ＋Ｈ］^＋、２．８４分（保持時間）

(3-Fluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) methanol (126 mg, 0.439 mmol) and 8 in N, N-dimethylformamide (DMF) (8 mL) To a solution of -chloro-1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (20 mg, 0.088 mmol), NaH (35.1 mg, .0. 878 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl and filtered. This solution was purified with MDAP to give the desired product as a white solid.
LC-MS (ESI): m / z 479 [M + H] ⁺ , 2.84 minutes (retention time)

E39
1-Methyl-8- [2- (4-trifluoromethyl-phenyl) -ethoxy] -1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（４‐（トリフルオロメチル）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３５４［Ｍ＋Ｈ］^＋、０．９４分（保持時間）

The title compound or a salt thereof is prepared by 2- (4- (trifluoromethyl) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 ( Prepared in a similar procedure as described for E11 starting from 2H) -one.
LC-MS (ESI): m / z 354 [M + H] ⁺ , 0.94 minutes (retention time)

E40
8-((3,4-Difluorobenzyl) oxy) -1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（８ｍＬ）中の（３，４‐ジフルオロフェニル）メタノール（１１１ｍｇ、０．７６９ｍｍｏｌ）および８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（５０ｍｇ、０．２２０ｍｍｏｌ）の溶液へ、ＮａＨ（２６．３ｍｇ、０．６５９ｍｍｏｌ）を添加し、室温にて１時間攪拌した。この反応混合物を、飽和ＮＨ_４Ｃｌ水溶液を添加することで反応停止し、ろ過した。この溶液を、ＭＤＡＰで精製して、表題の生成物のＴＦＡ塩を白色固体として得た（２０ｍｇ、２０．３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３６［Ｍ＋Ｈ］^＋、２．２５分（保持時間）

(3,4-Difluorophenyl) methanol (111 mg, 0.769 mmol) and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido [1 in N, N-dimethylformamide (DMF) (8 mL) , 6-a] pyrimidin-6 (2H) -one (50 mg, 0.220 mmol) was added NaH (26.3 mg, 0.659 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl and filtered. The solution was purified with MDAP to give the TFA salt of the title product as a white solid (20 mg, 20.3%).
LC-MS (ESI): m / z 336 [M + H] ⁺ , 2.25 minutes (retention time)

E41
8-((4-Chlorobenzyl) oxy) -1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐クロロフェニル）メタノールおよび８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３３４［Ｍ＋Ｈ］^＋、２．４２分（保持時間）

Starting from the title compound or its salt from (4-chlorophenyl) methanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared by a procedure similar to that described for E2.
LC-MS (ESI): m / z 334 [M + H] ⁺ , 2.42 minutes (retention time)

E42
Isopropyl-8-((3,4,5-trifluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

Ｎ，Ｎ‐ジメチルホルムアミド（ＤＭＦ）（８ｍＬ）中の（３，４，５‐トリフルオロフェニル）メタノール（２１４ｍｇ、１．３１８ｍｍｏｌ）および８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（５０ｍｇ、０．２２０ｍｍｏｌ）の溶液へ、ＮａＨ（５２．７ｍｇ、１．３１８ｍｍｏｌ）を添加し、室温にて１時間攪拌した。この反応混合物を、飽和ＮＨ_４Ｃｌを添加することで反応停止し、続いてろ過した。この溶液を、ＭＤＡＰで精製して、表題の化合物のＴＦＡ塩を得た（５ｍｇ、４．８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３５４［Ｍ＋Ｈ］^＋、２．４５分（保持時間）

(3,4,5-trifluorophenyl) methanol (214 mg, 1.318 mmol) and 8-chloro-1-isopropyl-3,4-dihydro-1H- in N, N-dimethylformamide (DMF) (8 mL) To a solution of pyrimido [1,6-a] pyrimidin-6 (2H) -one (50 mg, 0.220 mmol) was added NaH (52.7 mg, 1.318 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated NH ₄ Cl and subsequently filtered. This solution was purified by MDAP to give the TFA salt of the title compound (5 mg, 4.8%).
LC-MS (ESI): m / z 354 [M + H] ⁺ , 2.45 minutes (retention time)

E43
8- [2- (3,4-Dichloro-phenyl) -ethoxy] -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（３，４‐ジクロロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３５４［Ｍ＋Ｈ］＋、１．０５２分（保持時間）

The title compound or salt thereof is converted to 2- (3,4-dichlorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- Starting from ON, the procedure was similar to that described for E11.
LC-MS (ESI): m / z 354 [M + H] +, 1.052 minutes (retention time)

E44
1-Methyl-8- [2- (3,4,5-trifluoro-phenyl) -ethoxy] -1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（３，４，５‐トリフルオロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３４０［Ｍ＋Ｈ］＋、０．９０８分（保持時間）

The title compound or salt thereof is converted to 2- (3,4,5-trifluorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6. Prepared in a similar procedure as described for E11 starting from (2H) -one.
LC-MS (ESI): m / z 340 [M + H] +, 0.908 minutes (retention time)

E45
8- [2- (2,3-Difluoro-phenyl) -ethoxy] -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（２，３‐ジフルオロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２２［Ｍ＋Ｈ］^＋、０．６３２分（保持時間）

The title compound or salt thereof is converted to 2- (2,3-difluorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -Made from a procedure similar to that described for E11 starting from ON.
LC-MS (ESI): m / z 322 [M + H] ⁺ , 0.632 minutes (retention time)

E46
8- [2- (2,4-Difluoro-phenyl) -ethoxy] -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（２，４‐ジフルオロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２２［Ｍ＋Ｈ］^＋、１．０６分（保持時間）

The title compound or salt thereof is converted to 2- (2,4-difluorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -Made from a procedure similar to that described for E11 starting from ON.
LC-MS (ESI): m / z 322 [M + H] ⁺ , 1.06 minutes (retention time)

E47
8- (3-Fluoro-4-methylphenethyl) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（３‐フルオロ‐４‐メチルフェニル）エタノールおよび８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１８［Ｍ＋Ｈ］＋、０．７９分（保持時間）

The title compound or a salt thereof is prepared by 2- (3-fluoro-4-methylphenyl) ethanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 ( Prepared in a similar procedure as described for E11 starting from 2H) -one.
LC-MS (ESI): m / z 318 [M + H] +, 0.79 minutes (retention time)

E48
3- [2- (1-Methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimido [1,6-a] pyrimidin-8-yloxy) -ethyl] -benzonitrile

表題の化合物またはその塩を、３‐（２‐ヒドロキシエチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３４０［Ｍ＋Ｈ］＋、０．９０８分（保持時間）

The title compound or a salt thereof is converted to 3- (2-hydroxyethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- Starting from ON, the procedure was similar to that described for E11.
LC-MS (ESI): m / z 340 [M + H] +, 0.908 minutes (retention time)

E49
8- [2- (4-Chloro-phenyl) -ethoxy] -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、２‐（４‐クロロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１１［Ｍ＋Ｈ］＋、０．４０１分（保持時間）

Title compound or salt thereof from 2- (4-chlorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting and made in a similar procedure as described for E11.
LC-MS (ESI): m / z 311 [M + H] +, 0.401 minutes (retention time)

E50
8-((3-Fluoro-4- (trifluoromethyl) benzyl) oxy) -1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（トリフルオロメチル）フェニル）メタノールおよび８‐クロロ‐１‐イソプロピル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３８６［Ｍ＋Ｈ］^＋、２．６３分（保持時間）

The title compound or salt thereof is converted to (3-fluoro-4- (trifluoromethyl) phenyl) methanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine- Prepared in a similar procedure as described for E2, starting from 6 (2H) -one.
LC-MS (ESI): m / z 386 [M + H] ⁺ , 2.63 minutes (retention time)

E51
8- (2- (6- (3,4-difluorophenoxy) pyridin-3-yl) ethoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物またはその塩を、２‐（６‐（３，４‐ジフルオロフェノキシ）ピリジン‐３‐イル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１５［Ｍ＋１］^＋、２．４３（保持時間）

The title compound or a salt thereof can be synthesized from 2- (6- (3,4-difluorophenoxy) pyridin-3-yl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6 -A] Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 415 [M + 1] ⁺ , 2.43 (retention time)

E52
4- [2- (1-Methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrimido [1,6-a] pyrimidin-8-yloxy) -ethyl] -benzonitrile

表題の化合物またはその塩を、４‐（２‐ヒドロキシエチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１１［Ｍ＋Ｈ］＋、０．８６７分（保持時間）

The title compound or salt thereof is converted to 4- (2-hydroxyethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- Starting from ON, the procedure was similar to that described for E11.
LC-MS (ESI): m / z 311 [M + H] +, 0.867 minutes (retention time)

E53
5-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (3- (trifluoromethyl) Phenoxy) benzonitrile

水（５ｍＬ）および１，４‐ジオキサン（５．００ｍＬ）中の５‐（（（６‐（（３‐ブロモプロピル）アミノ）‐２‐クロロピリミジン‐４‐イル）オキシ）メチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリル（３５０ｍｇ、０．６４６ｍｍｏｌ）の溶液へ、Ｋ_２ＣＯ_３（１７９ｍｇ、１．２９２ｍｍｏｌ）を室温にて添加した。この反応混合物を、２時間５０℃に加熱した。この溶液を、水（０．３％ ＴＦＡ含有）およびＭｅＣＮを溶出液として用いた逆相カラムクロマトグラフィ（１２０ｇ）で精製して、５‐（（（６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐８‐イル）オキシ）メチル）‐２‐（３‐（トリフルオロメチル）フェノキシ）ベンゾニトリル，トリフルオロ酢酸塩を得た（１１ｍｇ、０．０２０ｍｍｏｌ、収率３．０６％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４３［Ｍ＋１］^＋、２．６９（保持時間）

5-((((6-((3-bromopropyl) amino) -2-chloropyrimidin-4-yl) oxy) methyl) -2- in water (5 mL) and 1,4-dioxane (5.00 mL) To a solution of (3- (trifluoromethyl) phenoxy) benzonitrile (350 mg, 0.646 mmol) was added K ₂ CO ₃ (179 mg, 1.292 mmol) at room temperature. The reaction mixture was heated to 50 ° C. for 2 hours. The solution was purified by reverse phase column chromatography (120 g) using water (containing 0.3% TFA) and MeCN as eluent to give 5-((((6-oxo-2,3,4,6- Tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile, trifluoroacetate was obtained (11 mg, 0. 020 mmol, yield 3.06%).
LC-MS (ESI): m / z 443 [M + 1] ⁺ , 2.69 (retention time)

E54
8- (2- (5- (3-Chloro-4- (trifluoromethyl) phenoxy) pyridin-2-yl) ethoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Pyrimidine-6 (2H) -one

表題の化合物またはその塩を、２‐（５‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）ピリジン‐２‐イル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４８１［Ｍ＋１］^＋、２．７４（保持時間）

The title compound or a salt thereof is converted to 2- (5- (4-chloro-3- (trifluoromethyl) phenoxy) pyridin-2-yl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H. -Prepared in a similar procedure as described for E2, starting from pyrimido [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 481 [M + 1] ⁺ , 2.74 (retention time)

E55
8- (4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４８０［Ｍ＋Ｈ］^＋、３．０８分（保持時間）

The title compound or a salt thereof is converted to 2- (4- (4-chloro-3- (trifluoromethyl) phenoxy) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 480 [M + H] ⁺ , 3.08 minutes (retention time)

E56
5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2-((6- Methylpyridin-3-yl) oxy) benzonitrile

表題の化合物またはその塩を、５‐（ヒドロキシメチル）‐２‐（（６‐メチルピリジン‐３‐イル）オキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋、１．６８分（保持時間）

The title compound or its salt is converted to 5- (hydroxymethyl) -2-((6-methylpyridin-3-yl) oxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido Prepared in a similar procedure as described for E2, starting from [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 404 [M + H] ⁺ , 1.68 minutes (retention time)

E57
Methyl-8- (4-((6- (trifluoromethyl) pyridin-2-yl) oxy) phenoxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、２‐（４‐（（６‐（トリフルオロメチル）ピリジン‐２‐イル）オキシ）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４７［Ｍ＋Ｈ］^＋、２．６８分（保持時間）

The title compound or a salt thereof is converted to 2- (4-((6- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H- Prepared in a similar procedure as described for E2, starting from pyrimido [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 447 [M + H] ⁺ , 2.68 minutes (retention time)

E58
8-((4- (3,5-difluorophenoxy) -3-fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、（４‐（３，５‐ジフルオロフェノキシ）‐３‐フルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１８［Ｍ＋Ｈ］^＋、２．７４分（保持時間）

The title compound or a salt thereof is converted to (4- (3,5-difluorophenoxy) -3-fluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 418 [M + H] ⁺ , 2.74 minutes (retention time)

E59
8- (3,4-Difluoro-benzylamino) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

ジメチルスルホキシド（ＤＭＳＯ）（２ｍＬ）中の８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（１００ｍｇ、０．５０１ｍｍｏｌ）および（３，４‐ジフルオロフェニル）メタナミン（８６ｍｇ、０．６０１ｍｍｏｌ）の空気中、室温での攪拌溶液へ、Ｋ_２ＣＯ_３（２０８ｍｇ、１．５０３ｍｍｏｌ）を添加した。この反応混合物を、１００℃にて１６時間攪拌した。この溶液をろ過し、ろ液を分取用ＨＰＬＣで精製して、表題の生成物のＴＦＡ塩を白色固体として得た（１００ｍｇ）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０７［Ｍ＋Ｈ］＋、０．９４分（保持時間）

8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (100 mg, 0.501 mmol) in dimethyl sulfoxide (DMSO) (2 mL) and To a stirred solution of (3,4-difluorophenyl) methanamine (86 mg, 0.601 mmol) in air at room temperature was added K ₂ CO ₃ (208 mg, 1.503 mmol). The reaction mixture was stirred at 100 ° C. for 16 hours. The solution was filtered and the filtrate was purified by preparative HPLC to give the TFA salt of the title product as a white solid (100 mg).
LC-MS (ESI): m / z 307 [M + H] +, 0.94 minutes (retention time)

E60
1-Methyl-8- (phenethylthio) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

ジメチルスルホキシド（ＤＭＳＯ）（３ｍＬ）中の８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（１００ｍｇ、０．５０１ｍｍｏｌ）および２‐フェニルエタンチオール（８３ｍｇ、０．６０１ｍｍｏｌ）の溶液へ、Ｋ_２ＣＯ_３（２０８ｍｇ、１．５０３ｍｍｏｌ）を添加した。この反応混合物を、１００℃にて１６時間攪拌した。粗生成物を、分取用ＨＰＬＣで精製して、表題の生成物７０ｍｇを得た。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ： ３０２（Ｍ＋Ｈ）＋、０．９１分（保持時間）

8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (100 mg, 0.501 mmol) in dimethyl sulfoxide (DMSO) (3 mL) and To a solution of 2-phenylethanethiol (83 mg, 0.601 mmol) was added K ₂ CO ₃ (208 mg, 1.503 mmol). The reaction mixture was stirred at 100 ° C. for 16 hours. The crude product was purified by preparative HPLC to give 70 mg of the title product.
LC-MS (ESI): m / z: 302 (M + H) +, 0.91 minutes (retention time)

E61
8- (4-Fluoro-benzylamino) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（４‐フルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋Ｈ］＋、０．９２分（保持時間）

Starting from the title compound or its salt from (4-fluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared by a procedure similar to that described for E59.
LC-MS (ESI): m / z 289 [M + H] +, 0.92 minutes (retention time)

E62
1-Methyl-8-((2-methylbenzyl) thio) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

テトラヒドロフラン（ＴＨＦ）（５ｍＬ）中の８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（２００ｍｇ、１．００２ｍｍｏｌ）およびｏ‐トリルメタンチオール（１６６ｍｇ、１．２０２ｍｍｏｌ）の、空気中、室温での攪拌懸濁液へ、カリウムｔｅｒｔ‐ブトキシド（１１２ｍｇ、１．００２ｍｍｏｌ）を一度に添加した。この反応混合物を、室温にて３時間攪拌した。得られた混合物を、濃縮し、分取用ＨＰＬＣで精製して、５０ｍｇの１‐メチル‐８‐（（２‐メチルベンジル）チオ）‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンを得た（５０ｍｇ、０．１５８ｍｍｏｌ、収率１５．７３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０２［Ｍ＋Ｈ］＋、１．２２分（保持時間）

8-Chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one (200 mg, 1.002 mmol) and o in tetrahydrofuran (THF) (5 mL) To a stirred suspension of -tolylmethanethiol (166 mg, 1.202 mmol) in air at room temperature was added potassium tert-butoxide (112 mg, 1.002 mmol) in one portion. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated and purified by preparative HPLC to give 50 mg of 1-methyl-8-((2-methylbenzyl) thio) -3,4-dihydro-1H-pyrimido [1,6- a] Pyrimidin-6 (2H) -one was obtained (50 mg, 0.158 mmol, 15.73% yield).
LC-MS (ESI): m / z 302 [M + H] +, 1.22 minutes (retention time)

E63
8-((2-Chlorobenzyl) thio) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（２‐クロロフェニル）メタンチオールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ６２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２２［Ｍ＋Ｈ］＋、１．２３分（保持時間）

Starting from the title compound or its salt from (2-chlorophenyl) methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared in a similar procedure as described for E62.
LC-MS (ESI): m / z 322 [M + H] +, 1.23 minutes (retention time)

E64
8-((2,4-Difluorobenzyl) amino) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（２，４‐ジフルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＤＡＤ）：ｍ／ｚ ３０７．１［Ｍ＋Ｈ］^＋、０．９３５分（保持時間）

The title compound or salt thereof is converted to (2,4-difluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting from, the procedure was similar to that described for E59.
LC-MS (DAD): m / z 307.1 [M + H] ⁺ , 0.935 minutes (retention time)

E65
8-((3,5-difluorobenzyl) amino) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３，５‐ジフルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＤＡＤ）：ｍ／ｚ ３０７．１［Ｍ＋Ｈ］^＋、０．９３３分（保持時間）

The title compound or a salt thereof is converted to (3,5-difluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting from, the procedure was similar to that described for E59.
LC-MS (DAD): m / z 307.1 [M + H] ⁺ , 0.933 minutes (retention time)

E66
8- (4-Fluoro-benzylsulfanyl) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（４‐フルオロフェニル）メタンチオールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ６２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０６［Ｍ＋Ｈ］＋、１．５１分（保持時間）

The title compound or salt thereof is obtained from (4-fluorophenyl) methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting and made in a similar procedure as described for E62.
LC-MS (ESI): m / z 306 [M + H] +, 1.51 minutes (retention time)

E67
8- (4-Chloro-benzylsulfanyl) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（４‐クロロフェニル）メタンチオールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ６２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２２［Ｍ＋Ｈ］＋、０．６９分（保持時間）

Starting from the title compound or its salt from (4-chlorophenyl) methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared in a similar procedure as described for E62.
LC-MS (ESI): m / z 322 [M + H] +, 0.69 minutes (retention time)

E68
8- (4-Chloro-3-fluoro-benzylamino) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（４‐クロロ‐３‐フルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２３［Ｍ＋Ｈ］^＋、０．７８分（保持時間）

The title compound or salt thereof is converted to (4-chloro-3-fluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -Made from a procedure similar to that described for E59, starting from ON.
LC-MS (ESI): m / z 323 [M + H] ⁺ , 0.78 minutes (retention time)

E69
8- (3-Fluoro-benzylamino) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（３‐フルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２８９［Ｍ＋Ｈ］＋、０．９１８分（保持時間）

Starting from the title compound or its salt from (3-fluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared by a procedure similar to that described for E59.
LC-MS (ESI): m / z 289 [M + H] +, 0.918 minutes (retention time)

E70
1-Methyl-8- (thiophen-2-ylmethylsulfanyl) -1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、チオフェン‐２‐イルメタンチオールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ６２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９４［Ｍ＋Ｈ］＋、０．８６分（保持時間）

Starting with the title compound or salt thereof from thiophen-2-ylmethanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one And was prepared in a similar procedure as described for E62.
LC-MS (ESI): m / z 294 [M + H] +, 0.86 minutes (retention time)

E71
8- (2,3-Difluoro-benzylamino) -1-methyl-1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（２，３‐ジフルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０７［Ｍ＋Ｈ］＋、０．６０分（保持時間）

The title compound or salt thereof is converted to (2,3-difluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one Starting from, the procedure was similar to that described for E59.
LC-MS (ESI): m / z 307 [M + H] +, 0.60 minutes (retention time)

E72
1-Methyl-8- (3,4,5-trifluoro-benzylamino) -1,2,3,4-tetrahydro-pyrimido [1,6-a] pyrimidin-6-one

表題の化合物またはその塩を、（３，４，５‐トリフルオロフェニル）メタナミンおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ５９についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３２５［Ｍ＋Ｈ］＋、０．７３分（保持時間）

The title compound or salt thereof is converted to (3,4,5-trifluorophenyl) methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H Prepared in a similar procedure as described for E59 starting from) -one.
LC-MS (ESI): m / z 325 [M + H] +, 0.73 minutes (retention time)

E73
1-Methyl-8- (4- (3- (trifluoromethyl) phenoxy) phenethyl) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

メタノール（１５ｍＬ）中の８‐（（４‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）エチニル）‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オン（２０ｍｇ、０．０４３ｍｍｏｌ）の溶液へ、炭素担持パラジウム（６ｍｇ、０．１０７ｍｍｏｌ）を添加した。この反応混合物を、室温にて１０分間Ａｒでパージした。この懸濁液を、水素ガスバルーンで処理した。１時間後、この反応混合物を、ろ過し、濃縮した。残渣をＭＤＡＰで精製して、表題の化合物のＴＦＡ塩を淡黄色オイルとして得た（１３ｍｇ、２２．３％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３０［Ｍ＋Ｈ］^＋、２．９１分（保持時間）

8-((4- (4-Chloro-3- (trifluoromethyl) phenoxy) phenyl) ethynyl) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a in methanol (15 mL) To a solution of pyrimidin-6 (2H) -one (20 mg, 0.043 mmol) was added palladium on carbon (6 mg, 0.107 mmol). The reaction mixture was purged with Ar at room temperature for 10 minutes. This suspension was treated with a hydrogen gas balloon. After 1 hour, the reaction mixture was filtered and concentrated. The residue was purified with MDAP to give the TFA salt of the title compound as a pale yellow oil (13 mg, 22.3%).
LC-MS (ESI): m / z 430 [M + H] ⁺ , 2.91 minutes (retention time)

E74
8-((3-Fluoro-4- (4-fluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（４‐フルオロフェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４００［Ｍ＋Ｈ］^＋、２．５０分（保持時間）

The title compound or salt thereof is converted to (3-fluoro-4- (4-fluorophenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine Prepared in a similar procedure as described for E2, starting from -6 (2H) -one.
LC-MS (ESI): m / z 400 [M + H] ⁺ , 2.50 minutes (retention time)

E75
8-((3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] Pyrimidine-6 (2H) -one

（３，５‐ジフルオロ‐４‐（（６‐（トリフルオロメチル）ピリジン‐３‐イル）オキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５５［Ｍ＋１］^＋、２．６０（保持時間）

(3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) phenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials as in D54, followed by The title compound or salt thereof was prepared by hydrolysis as described in D55 and cyclization as described in E53.
LC-MS (ESI): m / z 455 [M + 1] ⁺ , 2.60 (retention time)

E76
5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (pyridine-3 -Iloxy) benzonitrile

表題の化合物またはその塩を、５‐（ヒドロキシメチル）‐２‐（ピリジン‐３‐イルオキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３９０［Ｍ＋Ｈ］^＋、１．７０分（保持時間）

The title compound or salt thereof is converted to 5- (hydroxymethyl) -2- (pyridin-3-yloxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 390 [M + H] ⁺ , 1.70 minutes (retention time)

E77
1-methyl-8-((4- (3- (trifluoromethyl) phenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３２［Ｍ＋Ｈ］^＋、２．８１分（保持時間）

The title compound or salt thereof is converted to (4- (3- (trifluoromethyl) phenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine Prepared in a similar procedure as described for E2, starting from -6 (2H) -one.
LC-MS (ESI): m / z 432 [M + H] ⁺ , 2.81 minutes (retention time)

E78
8-((3,5-difluoro-4- (3-fluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（３‐フルオロフェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１８［Ｍ＋１］^＋、２．６５（保持時間）

The title compound or salt thereof is converted to (3,5-difluoro-4- (3-fluorophenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 418 [M + 1] ⁺ , 2.65 (retention time)

E79
8-((4- (3,5-difluorophenoxy) -3,5-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物またはその塩を、（４‐（３，５‐ジフルオロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３６［Ｍ＋１］^＋、２．７３（保持時間）

The title compound or a salt thereof is converted to (4- (3,5-difluorophenoxy) -3,5-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6 -A] Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 436 [M + 1] ⁺ , 2.73 (retention time)

E80
2- (3-Fluorophenoxy) -5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) Methyl) benzonitrile

表題の化合物またはその塩を、２‐（３‐フルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０７［Ｍ＋Ｈ］^＋、２．４６分（保持時間）

The title compound or salt thereof is converted to 2- (3-fluorophenoxy) -5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a]. Made in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 407 [M + H] ⁺ , 2.46 minutes (retention time)

E81
8-((3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６８［Ｍ＋１］^＋、２．９５（保持時間）

The title compound or salt thereof is converted to (3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 468 [M + 1] ⁺ , 2.95 (retention time)

E82
8-((4- (4-Chloro-3-fluorophenoxy) -3,5-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

表題の化合物またはその塩を、（４‐（４‐クロロ‐３‐フルオロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５２［Ｍ＋１］^＋、２．９２（保持時間）

The title compound or a salt thereof is converted to (4- (4-chloro-3-fluorophenoxy) -3,5-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 452 [M + 1] ⁺ , 2.92 (retention time)

E83
8-((4- (3-Chloro-4-fluorophenoxy) -3,5-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

表題の化合物またはその塩を、（４‐（３‐クロロ‐４‐フルオロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４５２［Ｍ＋１］^＋、２．８８（保持時間）

The title compound or a salt thereof is converted to (4- (3-chloro-4-fluorophenoxy) -3,5-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 452 [M + 1] ⁺ , 2.88 (retention time)

E84
2- (3-Chloro-4-fluorophenoxy) -5-(((1-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine-8- Yl) oxy) methyl) benzonitrile

表題の化合物またはその塩を、２‐（３‐クロロ‐４‐フルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４１［Ｍ＋１］^＋、２．６９（保持時間）

The title compound or a salt thereof is converted to 2- (3-chloro-4-fluorophenoxy) -5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] Pyrimidin-6 (2H) -one was made in a similar procedure as described for E2 starting from 6
LC-MS (ESI): m / z 441 [M + 1] ⁺ , 2.69 (retention time)

E85
3- (2-Fluoro-4-(((1-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) Phenoxy) benzonitrile

表題の化合物またはその塩を、３‐（２‐フルオロ‐４‐（ヒドロキシメチル）フェノキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０７［Ｍ＋Ｈ］^＋、２．３７分（保持時間）

The title compound or salt thereof is converted to 3- (2-fluoro-4- (hydroxymethyl) phenoxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a]. Made in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 407 [M + H] ⁺ , 2.37 minutes (retention time)

E86
5-(((1-Methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2- (pyrimidine-5 -Iloxy) benzonitrile

表題の化合物またはその塩を、５‐（ヒドロキシメチル）‐２‐（ピリミジン‐５‐イルオキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３９１［Ｍ＋Ｈ］^＋、１．７７分（保持時間）

The title compound or salt thereof is converted to 5- (hydroxymethyl) -2- (pyrimidin-5-yloxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 391 [M + H] ⁺ , 1.77 minutes (retention time)

E87
8-((3,5-difluoro-4- (4-fluorophenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（４‐フルオロフェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１８［Ｍ＋１］^＋、２．６８（保持時間）

The title compound or salt thereof is converted to (3,5-difluoro-4- (4-fluorophenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 418 [M + 1] ⁺ , 2.68 (retention time)

E88
8-((3,5-difluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Pyrimidine-6 (2H) -one

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（４‐フルオロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４８６［Ｍ＋１］^＋、３．００（保持時間）

The title compound or salt thereof is converted to (3,5-difluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H. -Prepared in a similar procedure as described for E2, starting from pyrimido [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 486 [M + 1] ⁺ , 3.00 (retention time)

E89
8-((3,5-difluoro-4- (4- (trifluoromethyl) phenoxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（４‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６８［Ｍ＋１］^＋、２．９８（保持時間）

The title compound or salt thereof is converted to (3,5-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 468 [M + 1] ⁺ , 2.98 (retention time)

E90
8-((4- (3-Chlorophenoxy) -3,5-difluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、（４‐（３‐クロロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３４［Ｍ＋１］^＋、２．８８（保持時間）

The title compound or a salt thereof is converted to (4- (3-chlorophenoxy) -3,5-difluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 434 [M + 1] ⁺ , 2.88 (retention time)

E91
8-((4- (3,4-difluorophenoxy) -3,5-difluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

（４‐（３，４‐ジフルオロフェノキシ）‐３，５‐ジフルオロフェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４２２［Ｍ＋Ｈ］^＋、２．５９分（保持時間）

(4- (3,4-Difluorophenoxy) -3,5-difluorophenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials as in D54, followed by hydrolysis as described in D55, and E53 The title compound or a salt thereof was prepared by carrying out the cyclization described in 1.
LC-MS (ESI): m / z 422 [M + H] ⁺ , 2.59 minutes (retention time)

E92
5-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) -2-((5- (trifluoromethyl ) Pyridin-2-yl) oxy) benzonitrile

５‐（ヒドロキシメチル）‐２‐（（５‐トリフルオロメチル）ピリジン‐２‐イル）オキシ）ベンゾニトリルおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４４［Ｍ＋Ｈ］^＋、２．４７分（保持時間）

5- (Hydroxymethyl) -2-((5-trifluoromethyl) pyridin-2-yl) oxy) benzonitrile and 2,4,6-trichloropyrimidine were used as starting materials like D54, followed by D55 The title compound or salt thereof was made by the described hydrolysis and the cyclization described in E53.
LC-MS (ESI): m / z 444 [M + H] ⁺ , 2.47 minutes (retention time)

E93
8-((3,5-difluoro-4- (4-fluoro-3- (trifluoromethyl) phenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H) -ON

（３，５‐ジフルオロ‐４‐（３‐フルオロ‐４‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４７２［Ｍ＋Ｈ］^＋、２．８０分（保持時間）

(3,5-difluoro-4- (3-fluoro-4- (trifluoromethyl) phenoxy) phenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials as in D54 and subsequently described in D55 And the cyclization described in E53 was performed to produce the title compound or a salt thereof.
LC-MS (ESI): m / z 472 [M + H] ⁺ , 2.80 minutes (retention time)

E94
2- (3,4-Difluorophenoxy) -5-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) Benzonitrile

２‐（３，４‐ジフルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１１［Ｍ＋Ｈ］^＋、２．３８分（保持時間）

2- (3,4-Difluorophenoxy) -5- (hydroxymethyl) benzonitrile and 2,4,6-trichloropyrimidine were used as starting materials like D54, followed by hydrolysis as described in D55, and E53. The title compound or salt thereof was made by performing the described cyclization.
LC-MS (ESI): m / z 411 [M + H] ⁺ , 2.38 minutes (retention time)

E95
8-((4-((6-chloropyridin-3-yl) oxy) -3-fluorobenzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine- 6 (2H) -On

表題の化合物またはその塩を、（４‐（（６‐クロロピリジン‐３‐イル）オキシ）‐３‐フルオロフェニル）メタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１７［Ｍ＋１］^＋、２．３８（保持時間）

The title compound or a salt thereof is converted to (4-((6-chloropyridin-3-yl) oxy) -3-fluorophenyl) methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [ Made from a similar procedure as described for E2, starting from 1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 417 [M + 1] ⁺ , 2.38 (retention time)

E96
2- (4-Chloro-3-fluorophenoxy) -5-(((1-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine-8- Yl) oxy) methyl) benzonitrile

表題の化合物またはその塩を、２‐（４‐クロロ‐３‐フルオロフェノキシ）‐５‐（ヒドロキシメチル）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４１［Ｍ＋１］^＋、２．７１（保持時間）

The title compound or salt thereof is converted to 2- (4-chloro-3-fluorophenoxy) -5- (hydroxymethyl) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] Pyrimidin-6 (2H) -one was made in a similar procedure as described for E2 starting from 6
LC-MS (ESI): m / z 441 [M + 1] ⁺ , 2.71 (retention time)

E97
8-((4- (4-Chloro-3- (trifluoromethyl) phenoxy) -3-fluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H )-on

表題の化合物またはその塩を、［４‐（４‐クロロ‐３‐トリフルオロメチル‐フェノキシ）‐３‐フルオロ‐フェニル］‐メタノールおよび２，４，６‐トリクロロピリミジンから出発して、Ｅ５３についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４７０［Ｍ＋Ｈ］^＋、２．９８分（保持時間）

Starting from [4- (4-Chloro-3-trifluoromethyl-phenoxy) -3-fluoro-phenyl] -methanol and 2,4,6-trichloropyrimidine, the title compound or salt thereof is obtained. Produced in a similar procedure as described.
LC-MS (ESI): m / z 470 [M + H] ⁺ , 2.98 minutes (retention time)

E98
3-Fluoro-5- (2-fluoro-4-(((1-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) Oxy) methyl) phenoxy) benzonitrile

表題の化合物またはその塩を、３‐フルオロ‐５‐（２‐フルオロ‐４‐（ヒドロキシメチル）フェノキシ）ベンゾニトリルおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４２５［Ｍ＋１］^＋、２．５９（保持時間）

The title compound or salt thereof can be converted to 3-fluoro-5- (2-fluoro-4- (hydroxymethyl) phenoxy) benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] Pyrimidin-6 (2H) -one was made in a similar procedure as described for E2 starting from 6
LC-MS (ESI): m / z 425 [M + 1] ⁺ , 2.59 (retention time)

E99
8-((3,4-Difluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

（３，４‐ジフルオロフェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ２９４［Ｍ＋１］^＋、１．８６（保持時間）

Using (3,4-difluorophenyl) methanol and 2,4,6-trichloropyrimidine as starting materials as in D54, followed by hydrolysis as described in D55 and cyclization as described in E53 Or a salt thereof.
LC-MS (ESI): m / z 294 [M + 1] ⁺ , 1.86 (retention time)

E100
8-((4- (4-Fluoro-3- (trifluoromethyl) phenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

（４‐（４‐フルオロ‐３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３６［Ｍ＋Ｈ］^＋、２．８３分（保持時間）

(4- (4-Fluoro-3- (trifluoromethyl) phenoxy) phenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials like D54, followed by hydrolysis as described in D55, and E53 The title compound or a salt thereof was prepared by carrying out the cyclization described in 1.
LC-MS (ESI): m / z 436 [M + H] ⁺ , 2.83 minutes (retention time)

E101
8-((3-Fluoro-4- (3- (trifluoromethyl) phenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

（３‐フルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３６［Ｍ＋Ｈ］^＋、２．７６分（保持時間）

(3-Fluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials like D54, followed by hydrolysis as described in D55, and E53 The title compound or a salt thereof was prepared by carrying out the cyclization described in 1.
LC-MS (ESI): m / z 436 [M + H] ⁺ , 2.76 minutes (retention time)

E102
8- (4- (4-Chloro-3-fluorophenoxy) -3-fluorophenoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine-6 (2H)- on

表題の化合物またはその塩を、２‐（４‐（４‐クロロ‐３‐フルオロフェノキシ）‐３‐フルオロフェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４４８［Ｍ＋１］^＋、２．８８（保持時間）

The title compound or a salt thereof is converted to 2- (4- (4-chloro-3-fluorophenoxy) -3-fluorophenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 448 [M + 1] ⁺ , 2.88 (retention time)

E103
8- (4- (4-Chloro-3-fluorophenoxy) phenoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（４‐（３‐クロロ‐４‐フルオロフェノキシ）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３０［Ｍ＋１］^＋、２．８２（保持時間）

The title compound or a salt thereof can be synthesized from 2- (4- (3-chloro-4-fluorophenoxy) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a Prepared in a similar procedure as described for E2, starting from pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 430 [M + 1] ⁺ , 2.82 (retention time)

E104
4- (2-cyano-4-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) phenoxy) -2 -Fluorobenzonitrile

４‐（２‐シアノ‐４‐（ヒドロキシメチル）フェノキシ）‐２‐フルオロベンゾニトリルおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１０［Ｍ＋Ｈ］^＋、２．２３分（保持時間）

4- (2-cyano-4- (hydroxymethyl) phenoxy) -2-fluorobenzonitrile and 2,4,6-trichloropyrimidine were used as starting materials as in D54, followed by hydrolysis as described in D55, and The title compound or a salt thereof was prepared by carrying out the cyclization described in E53.
LC-MS (ESI): m / z 410 [M + H] ⁺ , 2.23 minutes (retention time)

E105
8- (3-Fluoro-4- (3- (trifluoromethyl) phenoxy) phenethyl) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（３‐フルオロ‐４‐（３‐（トリフルオロメチル）フェノキシ）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４６４［Ｍ＋１］^＋、２．９３（保持時間）

The title compound or salt thereof is converted to 2- (3-fluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1 , 6-a] pyrimidin-6 (2H) -one was made in a similar procedure as described for E2.
LC-MS (ESI): m / z 464 [M + 1] ⁺ , 2.93 (retention time)

E106
2-Chloro-4- (2-cyano-4-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidin-8-yl) oxy) methyl) Phenoxy) benzonitrile

２‐クロロ‐４‐（２‐シアノ‐４‐（ヒドロキシメチル）フェノキシ）ベンゾニトリルおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３４［Ｍ＋Ｈ］^＋、２．３６分（保持時間）

2-Chloro-4- (2-cyano-4- (hydroxymethyl) phenoxy) benzonitrile and 2,4,6-trichloropyrimidine are used as starting materials like D54, followed by hydrolysis as described in D55, and The title compound or a salt thereof was prepared by carrying out the cyclization described in E53.
LC-MS (ESI): m / z 434 [M + H] ⁺ , 2.36 minutes (retention time)

E107
2- (4-Chloro-3- (trifluoromethyl) phenoxy) -5-(((6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine-8- Yl) oxy) methyl) benzonitrile

２‐（４‐クロロ‐３‐（トリフルオロメチル）フェノキシ）‐５‐（ヒドロキシメチル）フェノキシ）ベンゾニトリルおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４７７［Ｍ＋Ｈ］^＋、２．７８分（保持時間）

2- (4-Chloro-3- (trifluoromethyl) phenoxy) -5- (hydroxymethyl) phenoxy) benzonitrile and 2,4,6-trichloropyrimidine were used as starting materials as in D54, followed by D55. The title compound or salt thereof was made by the described hydrolysis and the cyclization described in E53.
LC-MS (ESI): m / z 477 [M + H] ⁺ , 2.78 minutes (retention time)

E108
8-((4- (3-Fluoro-4-methylphenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３‐フルオロ‐４‐メチルフェノキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンから出発して、Ｅ５３についての記載に類似の手順で作製した。（４‐（３‐フルオロ‐４‐メチルフェノキシ）フェニル）メタノールおよび２，４，６‐トリクロロピリミジンをＤ５４のように出発物質として用い、続いてＤ５５に記載の加水分解、そしてＥ５３に記載の環化を行うことで、表題の化合物またはその塩を作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３８２［Ｍ＋１］^＋、２．７０（保持時間）

The title compound or salt thereof was made in a similar procedure as described for E53 starting from (4- (3-fluoro-4-methylphenoxy) phenyl) methanol and 2,4,6-trichloropyrimidine. (4- (3-Fluoro-4-methylphenoxy) phenyl) methanol and 2,4,6-trichloropyrimidine were used as starting materials as in D54, followed by hydrolysis as described in D55 and ring as described in E53. The title compound or a salt thereof was prepared by carrying out the conversion.
LC-MS (ESI): m / z 382 [M + 1] ⁺ , 2.70 (retention time)

E109
8- (2- (5- (3,4-Difluorophenoxy) -4-fluoropyridin-2-yl) ethoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine -6 (2H) -On

表題の化合物またはその塩を、２‐（６‐（３，４‐ジフルオロフェノキシ）‐５‐フルオロピリジン‐３‐イル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４３３［Ｍ＋Ｈ］^＋、２．５９分（保持時間）

The title compound or a salt thereof is converted to 2- (6- (3,4-difluorophenoxy) -5-fluoropyridin-3-yl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido Prepared in a similar procedure as described for E2, starting from [1,6-a] pyrimidin-6 (2H) -one.
LC-MS (ESI): m / z 433 [M + H] ⁺ , 2.59 minutes (retention time)

E110
8- (4- (3,4-Difluorophenoxy) phenoxy) -1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（４‐（３，４‐ジフルオロフェノキシ）フェニル）エタノールおよび８‐クロロ‐１‐メチル‐３，４‐ジヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐６（２Ｈ）‐オンから出発して、Ｅ２についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４１４［Ｍ＋Ｈ］^＋、２．６８分（保持時間）

The title compound or a salt thereof is converted to 2- (4- (3,4-difluorophenoxy) phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido [1,6-a] pyrimidine Prepared in a similar procedure as described for E2, starting from -6 (2H) -one.
LC-MS (ESI): m / z 414 [M + H] ⁺ , 2.68 minutes (retention time)

E111
8- (3,4-Difluorophenethyl) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

ＴＨＦ（５ｍＬ）中の２‐（３，４‐ジフルオロフェニル）エタノール（２２１ｍｇ、１．４００ｍｍｏｌ）の溶液へ、ＮａＨ（１１２ｍｇ、２．８０ｍｍｏｌ）を０℃にて添加した。この反応混合物を、０℃にて１０分間攪拌し、次に、ｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレート（４００ｍｇ、１．４００ｍｍｏｌ）を添加し、０℃にてさらに０．５時間攪拌した。この混合物を、氷水へ注ぎ入れ、ＤＣＭ（１０ｍＬ×３）で抽出した。一つにまとめた抽出物を、水（１０ｍＬ）、続いて鹹水（１０ｍＬ）で洗浄し、次にＮａ_２ＳＯ_４上で乾燥した。この混合物を濃縮して、ｔｅｒｔ‐ブチル８‐（３，４‐ジフルオロフェネトキシ）‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートを得た。１，４‐ジオキサン（１０ｍＬ）中の粗化合物の溶液に、４Ｎ ＨＣｌを添加し、室温にて３時間攪拌し、続いて濃縮した。残渣をＭＤＡＰで精製して、表題の生成物のＨＣｌ塩を白色固体として得た（４６ｍｇ、収率１０．８％）。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３０８［Ｍ＋Ｈ］^＋、０．９４分（保持時間）

To a solution of 2- (3,4-difluorophenyl) ethanol (221 mg, 1.400 mmol) in THF (5 mL) was added NaH (112 mg, 2.80 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine- 1-Carboxylate (400 mg, 1.400 mmol) was added and stirred at 0 ° C. for a further 0.5 hour. The mixture was poured into ice water and extracted with DCM (10 mL × 3). The combined extracts were washed with water (10 mL) followed by brine (10 mL) and then dried over Na ₂ SO ₄ . The mixture was concentrated to tert-butyl 8- (3,4-difluorophenoxy) -6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a] pyrimidine-1- Carboxylate was obtained. To a solution of the crude compound in 1,4-dioxane (10 mL) was added 4N HCl and stirred at room temperature for 3 hours, followed by concentration. The residue was purified by MDAP to give the HCl salt of the title product as a white solid (46 mg, 10.8% yield).
LC-MS (ESI): m / z 308 [M + H] ⁺ , 0.94 minutes (retention time)

E112
8- (3,4-Dichlorophenoxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、２‐（３，４‐ジクロロフェニル）エタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３４０［Ｍ＋Ｈ］^＋、１．０４分（保持時間）

The title compound or a salt thereof is converted to 2- (3,4-dichlorophenyl) ethanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6-a]. Prepared in a similar procedure as described for E111 starting from pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 340 [M + H] ⁺ , 1.04 minutes (retention time)

E113
8- (3,4,5-trifluorobenzyloxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３，４，５‐トリフルオロフェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３１２［Ｍ＋Ｈ］^＋、０．５１分（保持時間）

The title compound or a salt thereof is prepared from (3,4,5-trifluorophenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1,6- a] Made from a procedure similar to that described for E111 starting from pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 312 [M + H] ⁺ , 0.51 minutes (retention time)

E114
8-((3,5-difluoro-4- (4-fluorophenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（４‐フルオロフェノキシ）フェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋、０．９４分（保持時間）

The title compound or a salt thereof is converted to (3,5-difluoro-4- (4-fluorophenoxy) phenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H- Prepared in a similar procedure as described for E111 starting from pyrimido [1,6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 404 [M + H] ⁺ , 0.94 minutes (retention time)

E115
8-((3,5-difluoro-4- (3-fluorophenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３，５‐ジフルオロ‐４‐（３‐フルオロフェノキシ）フェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋、０．９３分（保持時間）

The title compound or a salt thereof is converted to (3,5-difluoro-4- (3-fluorophenoxy) phenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H- Prepared in a similar procedure as described for E111 starting from pyrimido [1,6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 404 [M + H] ⁺ , 0.93 minutes (retention time)

E116
8-((3-Fluoro-4- (3-fluorophenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（３‐フルオロフェノキシ）フェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３８６［Ｍ＋Ｈ］^＋、０．９０分（保持時間）

The title compound or a salt thereof is converted to (3-fluoro-4- (3-fluorophenoxy) phenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [ Made from a similar procedure as described for E111 starting from 1,6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 386 [M + H] ⁺ , 0.90 minutes (retention time)

E117
8-((4- (3,4-difluorophenoxy) -3-fluorobenzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３，４‐ジフルオロフェノキシ）‐３‐フルオロフェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋、０．９４分（保持時間）

The title compound or a salt thereof is converted to (4- (3,4-difluorophenoxy) -3-fluorophenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H- Prepared in a similar procedure as described for E111 starting from pyrimido [1,6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 404 [M + H] ⁺ , 0.94 minutes (retention time)

E118
8-((3-Fluoro-4- (4-fluorophenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（３‐フルオロ‐４‐（４‐フルオロフェノキシ）フェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３８６［Ｍ＋Ｈ］^＋、０．９２分（保持時間）

The title compound or a salt thereof is converted to (3-fluoro-4- (4-fluorophenoxy) phenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [ Made from a similar procedure as described for E111 starting from 1,6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 386 [M + H] ⁺ , 0.92 minutes (retention time)

E119
8-((4- (3,4-Difluorophenoxy) benzyl) oxy) -3,4-dihydro-1H-pyrimido [1,6-a] pyrimidin-6 (2H) -one

表題の化合物またはその塩を、（４‐（３，４‐ジフルオロフェノキシ）フェニル）メタノールおよびｔｅｒｔ‐ブチル８‐クロロ‐６‐オキソ‐２，３，４，６‐テトラヒドロ‐１Ｈ‐ピリミド［１，６‐ａ］ピリミジン‐１‐カルボキシレートから出発して、Ｅ１１１についての記載に類似の手順で作製した。
ＬＣ‐ＭＳ（ＥＳＩ）：ｍ／ｚ ３８６［Ｍ＋Ｈ］^＋、０．９３分（保持時間）

The title compound or a salt thereof is converted to (4- (3,4-difluorophenoxy) phenyl) methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido [1, Prepared in a similar procedure as described for E111 starting from 6-a] pyrimidine-1-carboxylate.
LC-MS (ESI): m / z 386 [M + H] ⁺ , 0.93 minutes (retention time)

D. Biological Assays and Data The compounds of the present invention are Lp-PLA ₂ inhibitors and are useful in the treatment of diseases mediated by Lp-PLA ₂ . The biological activity of the compounds of the present invention is measured using any suitable assay for measuring the activity of the compounds as Lp-PLA ₂ inhibitors and using tissue and in vivo models. May be.

  Biological activity data for each compound was reported as at least one experiment or as the average of multiple experiments. It is understood that the data described herein may have reasonable variations depending on the specific conditions and procedures used by the experimenter.

Lipoprotein-related phospholipase A2 (Lp-PLA ₂ ) biochemical assay (1) Recombinant human Lp-PLA ₂ assay (rhLp-PLA ₂ ) (also referred to as “PED6” assay)
N-((6- (2,4-dinitrophenyl) amino) -hexanoyl) -2- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacene-3 -Pentanoyl) -1-hexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt (PED6) is a commercially available fluorescently labeled phospholipid, which includes Invitrogene and molecular probes (Molecular Probes) ). A quenching paranitrophenyl (PNP) group is present at the sn3 position and a Bodipy fluorescein (FL) group is present at the sn2 position. When cleaved with lp-PLA _2, it is liberated Bodipy FL group, followed by an increase in fluorescence may be caused. Inhibitors of Lp-PLA ₂ thus prevent this cleavage and no increase in fluorescence is seen.

The PED6 assay was performed as an unquenched 10 μL assay. Source plates containing the compounds to be tested were made by serial dilutions of compounds 1: 3 (volume ratio) in DMSO on 384-well microplates. Next, 0.01 μL of the compound on the compound source plate was transferred to a 384 well Greiner 784076 (black) plate using an ECHO liquid dispenser. 5 μL of recombinant human Lp-PLA ₂ enzyme (4 nM (or 110 pM) rhLp-PLA ₂ in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well of the plate. The plate was centrifuged for 10 seconds at 500 rpm. After 30 min preincubation, 5 μL of substrate (4 μM (or 5 μM) PED6 [from 5 mM DMSO stock] in 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS assay buffer) in 384 well Greiner 784076 (black) Added to plate. The plate was centrifuged for 10 seconds at 500 rpm. The plate was covered with a light shield and incubated at room temperature for 20 minutes. Plate fluorescence intensity readings were performed using a ViewLux microplate imager for the Envision fluorescence spectrophotometer at ex: 480 / em: 540, and pIC50 data, curves, and QC analysis were performed using Excel's XL fitting module. went.

For all exemplified compounds of the present invention were tested according to a similar assay to that described above assays or above, it has been found to exhibit inhibitory activity against Lp-PLA _2. The compounds described below were generally tested according to the PED6 assay described above. The pIC ₅₀ value for each compound was reported as at least one experiment or as the average of multiple experiments. The upper limit of pIC ₅₀ obtained with this PED6 assay is 9.3. If a precise assay is used, a compound that exhibits a pIC ₅₀ equal to 9.3 in the PED6 assay described above may exhibit a pIC _{50 greater} than 9.3.

The pIC ₅₀ value in the PED6 assay for all example compounds was at least 5.0.

Examples 1-7, 10, 13-17, 21, 25, 28-30, 32, 34, 38, 40, 42, 53-56, 58, 74-85, 87-108, 110, and 113-119 The pIC ₅₀ value in the PED6 assay for was at least 8.0.

In the PED6 assay for Examples 3, 7, 53, 55, 56, 58, 75, 79, 80-84, 88, 90, 91, 93-98, 100-102, 104, 105, 107, and 114-119 The pIC ₅₀ value was at least 9.0.

  Table 1 below shows the pIC50 for some exemplary compounds.

(2) PLA2 VIIB assay PLA2 VIIB (new serine-dependent lipase (Novel Serine Dependent Lipase), NSDL ) is a serine hydrolase with 40% amino acid identity with the human Lp-PLA _2. Sequence comparison shows that the position of the active site catalytic triad of PLA VIIB is similar to that of Lp-PLA ₂ . Similar to Lp-PLA _2, it has the ability to hydrolyze oxidatively modified phospholipids and can be analyzed using known Lp-PLA ₂ substrates.

When cleaved with phospholipase, PLA2 VIIB releases the Bodipy group. In this assay, recombinant human PLA2 VIIB is used as a source of phospholipase, and compound screening is performed by testing its degree of inhibition in this assay. Using this assay, the degree of selectivity between the PLA2 VIIB and Lp-PLA ₂ of the test compound.

  The PLA2 VIIB assay was applied as a 10 μL assay without reaction termination. A source plate containing the compound is made by serially diluting the compound 1: 3 (volume ratio) in pure DMSO on a 384-well microplate. 0.01 μL of compound on the compound source plate was transferred to a 384 well Greiner 784076 (black) plate with an ECHO liquid dispenser. 5 μL of a novel serine-dependent lipase (NSDL) enzyme (50 nM HEPES, pH 7.4, 150 mM NaCl, 5 nM NSDL in 1 mM CHAPS assay buffer) was added to each well. The plate was centrifuged for 10 seconds at 500 rpm. After 30 minutes of pre-incubation, 5 μL of substrate (5 μM PED6 [from 5 mM DMSO stock] in 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS assay buffer) to a 384 well Greiner 784076 (black) low volume plate. Added. Plate kinetic readings were performed using a ViewLux microplate reader or Envision fluorescence spectrophotometer at ex: 480 / em: 540, starting reading immediately after addition of PED6. IC50 data (can be converted to pIC50 data), curves, and QC analysis were performed using Excel's XL fit module.

All exemplary compounds of the invention were tested in the PLA2 VIIB assay or an assay similar to that described above. In all tested compounds other than Examples 9, 11, 18-19, 22-24, 28, 36, 39, 43-52, 59-65, 67-73, 109, and 111, human recombinant Lp-PLA The selectivity between ₂ and PLA2 VIIB was over 100 times.

(3) Lipoprotein-related phospholipase A2 (Lp-PLA ₂ ) human plasma assay (also referred to as “thio-PAF assay”)
The human plasma assay utilizes a thioester analog of PAF (phosphatidylcholine), where hydrolysis leads to the formation of phospholipids containing free thiol groups. The amount of thiols is quantified continuously by reaction with CPM (7-diethylamino-3- (4'-malemidylphenyl) -4-methylcoumarin), a maleimide that increases fluorescence intensity by Michael addition of thiols. Is done. This assay allows the detection of Lp-PLA ₂ activity in human plasma as measured by specific inhibition by Lp-PLA ₂ inhibitors.

  The thio-PAF assay was performed as a quenched 15 μL assay. A compound source plate was made by serially diluting the compound 1: 3 (volume ratio) in pure DMSO on a 384-well microplate. 0.01 μL of compound on the compound source plate was transferred to a 384 well Greiner 784076 (black) low volume plate with an ECHO liquid dispenser. 8 μL of human plasma that had been collected in advance and stored in a frozen pool was added. The plate was centrifuged for 10 seconds at 500 rpm. After 30 min pre-incubation, 2.5 mM 2-thio-PAF [from ethanol stock], 32 μM CPM [from DMSO stock], and 3.2 mM in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS 2 μL of the substrate solution containing NEM (N-ethylmaleimide) [freshly prepared daily with DMSO] was added to a 384-well Greiner 784076 (black) low volume plate by a BRAVO liquid handling station. After 2 minutes, the reaction was quenched with 5 μL of 5% aqueous trifluoroacetic acid (TFA). The plate was covered and protected from light and incubated at room temperature for 40 minutes. The plate was read using an Envision microplate reader at ex: 380 / em: 485. pIC50 data, curves, and QC analysis were performed using Excel's XL fit module.

  All of the exemplary compounds of the invention were tested in a thio-PAF assay or an assay similar to that described above.

For all compounds except Examples 18, 19, 22-24, 39, 43, 45-50, 52, 57, 59-65, 67-73, the pIC ₅₀ value in the thio-PAF assay is at least 5 0.0.

Thio for Examples 1-10, 12, 13, 15-17, 20, 21, 25, 27-34, 37, 38, 40, 42, 53-56, 58, 66, 74-107, and 111-119 _{pIC 50} values in -PAF assay was at least 6.0.

Examples 1-5, 7, 10, 13, 15, 16, 21, 27-30, 33, 34, 37, 38, 40, 42, 53, 55, 56, 58, 75, 76, 79-84, The pIC ₅₀ values in the thio-PAF assay for 88, 89, 91-101, 104-107, and 112-119 were at least 7.0.

E. Compounds of the methods the present invention uses are inhibitors of Lp-PLA _2. Therefore, these compounds can be used in therapies, such as the treatment of disorders associated with Lp-PLA ₂ activity. Accordingly, another aspect of the present invention relates to a method of treating a condition associated with the activity of Lp-PLA _2. As it will be appreciated by those skilled in the art, a particular disease state or its treatment, including one or more of the mechanisms described herein, one or more fundamental mechanisms associated with Lp-PLA ₂ activity May be involved.

In certain embodiments, inhibitors of Lp-PLA ₂ according to the present invention can be used for the treatment of any of the disorders disclosed in the following published patent applications: WO 96/13484, WO 96/19451, WO 97/02242, WO97 / 12963, WO97 / 21675, WO97 / 21676, WO97 / 41098, WO97 / 41099, WO99 / 24420, WO00 / 10980, WO00 / 66566, WO00 / 66567, WO00 / 68208, WO01 / 60805, WO02 / 30904, WO02 / 30911, WO03 / 015786, WO03 / 016287, WO03 / 041712, WO03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 8708 8, WO08 / 048867, US2008 / 0103156, US2008 / 0090851, US2008 / 0090852, WO08 / 048866, WO05 / 003118 CA2530816 A1), WO06 / 063811, WO06 / 063813, WO2008 / 141176, JP200018847, US2008 / 0207847 0239565 A1, and US2008 / 0280829 A1.

  In certain embodiments, the compounds of the invention can be used in the treatment of any disease involving endothelial dysfunction, such as atherosclerosis (eg, peripheral vascular atherosclerosis and cerebrovascular atherosclerosis). Atherosclerosis), diabetes, hypertension, angina pectoris, and after ischemia-reperfusion.

  In certain embodiments, the compounds of the invention can be used to treat any disease involving lipid oxidation associated with enzyme activity, eg, in addition to pathologies such as atherosclerosis and diabetes, Other conditions such as rheumatism, stroke, inflammatory conditions of the brain such as Alzheimer's disease, schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.

In certain embodiments, the compounds of the present invention comprise activated monocytes, macrophages, including diseases involving activated macrophages such as M1, dendrites, and / or other macrophages that generate oxidative stress. Or all of these cell types express Lp-PLA ₂ and typical disorders include, but are not limited to, psoriasis Rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer's disease, and lupus And autoimmune diseases.

In certain embodiments, the present invention provides a method of treating a disease associated with the activity of Lp-PLA _2, the method, the subject in need thereof, a therapeutically effective inhibitor of Lp-PLA ₂ Including treating with an amount. Disease, monocytes, macrophages or increased involvement of lymphocytes, the formation of lysophosphatidylcholine and oxidized free fatty acid can be associated lipid oxidation in conjunction with Lp-PLA ₂ activity, or endothelial dysfunction.

  In other embodiments, the compounds of the invention may provide primary or secondary prevention of acute coronary events such as those caused by atherosclerosis, adjunct therapy in the prevention of restenosis, or diabetic or hypertensive Can be used to delay the progression of renal failure. Prevention includes treatment of a subject at risk for having such a condition.

  In certain embodiments, the compound of the invention comprises an anti-hyperlipidemic agent, an anti-atherosclerotic agent, an anti-diabetic agent, an anti-anginal agent, an anti-inflammatory agent, or an anti-hypertensive agent, or a lipoprotein (A) In combination with an agent for reducing (Lp (a)), it can be used for the treatment of the diseases described herein. Examples of the above include, but are not limited to, cholesterol synthesis inhibitors such as statins, antioxidants such as probucol, insulin resistance improvers, calcium channel antagonists, and non-steroidal anti-inflammatory drugs (NSAIDs). Inflammatory drugs. Examples of the agent for reducing Lp (a) include aminophosphonates described in WO97 / 02037, WO98 / 28310, WO98 / 28311, and WO98 / 28312.

  In one embodiment, the compounds of the invention can be used with one or more statins. Statins are a known class of cholesterol lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin, and rosuvastatin. These two agents may be administered substantially simultaneously or at different times according to the judgment of the physician.

  In certain embodiments, the compounds of the invention can be used with an antidiabetic agent or an insulin resistance ameliorating agent. In one embodiment, the compounds of the invention can be used with a PPAR gamma activator, exemplified by GI262570 (Glaxosmith Kline), and compounds of the glitazone class such as rosiglitazone, troglitazone, and pioglitazone.

In one embodiment, the compounds of the invention can be used to treat neurodegenerative diseases in a subject. The method comprises administering to a subject in need thereof, comprising administering a pharmaceutical composition comprising an agent that inhibits the activity of Lp-PLA _2. Representative neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In certain embodiments, the neurodegenerative diseases described herein are associated with blood brain barrier abnormalities. In one embodiment, the subject to whom an agent that inhibits the activity of Lp-PLA ₂ is administered is a human.

  In one embodiment, the present invention provides a method of treating a subject having or at risk for vascular dementia. The method includes administering to the subject a pharmaceutical composition comprising a safe effective amount of a compound of the invention. In certain embodiments, vascular dementia is associated with Alzheimer's disease.

  In certain embodiments, the present invention provides a method of treating a neurological disorder associated with blood brain barrier (BBB) dysfunction, inflammation, and / or microglia activation in a subject in need thereof. . The method includes administering to the subject a safe effective amount of a compound of the invention. In a further embodiment, the blood brain barrier abnormality is a blood brain barrier that can penetrate. In yet a further embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are, for example, but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In one embodiment, the present invention provides a method of treating a disease associated with a subject having a blood brain barrier (BBB) breakdown. Representative diseases include, but are not limited to, cerebral hemorrhage and cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In certain embodiments, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis (MS).

  In certain embodiments, the present invention provides a method of reducing accumulation in the brain of a subject of beta amyloid, designated “Aβ”. The method includes administering to a subject in need thereof a pharmaceutical composition comprising a safe effective amount of a compound of the invention. In a further embodiment, the beta amyloid is Abeta-42.

  In certain embodiments, when a safe effective amount of a compound of the invention is administered to a subject, the method can be useful in the treatment of a neurodegenerative disease where the subject is being treated or can be complicated. Administration of the therapeutic agent to a subject. For example, if the neurodegenerative disease is similar to Alzheimer's disease, the subject is ARICEPT (TM) or donepezil, COGNEX (TM) or tacrine, EXELON (TM) or rivastigmine, REMINYL (TM) or galantamine, anti-amyloid vaccine, Abeta It may be treated with other agents that target Alzheimer's disease, such as reduction therapeutics, mental exercise, or irritation.

  In certain embodiments, the invention relates to a method of treating a metabolic bone disease by administering a safe effective amount of a compound of the invention to a subject in need thereof. Exemplary metabolic bone diseases include, but are not limited to, diseases involving loss of bone mass and density, including osteoporosis and bone loss related diseases. Representative osteoporosis and bone loss related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases Is mentioned. In a further embodiment, the subject in need thereof is a human.

It is believed that the methods for preventing osteoporosis and / or osteopenia described herein can be affected by inhibition of Lp-PLA ₂ expression and / or inhibition of Lp-PLA ₂ protein activity. Accordingly, certain embodiments of the present invention provide methods for inhibiting Lp-PLA ₂ by blocking enzyme activity. In a further embodiment, a method for inhibiting Lp-PLA ₂ by reduction and / or downregulation of the expression of _Lp-PLA 2 RNA is provided. In a further embodiment, prevention or alleviation of symptoms associated with metabolic bone diseases such as osteoporosis and / or osteopenia can be achieved by preventing and / or reducing loss of bone mass and / or loss of bone density. Brought about.

  In certain embodiments, the method further comprises administering to a subject in need thereof an additional therapeutic agent used in the treatment of metabolic bone disease. For example, if the metabolic bone disease is osteoporosis, bisphosphate (eg, alendronate, ibandromate, risedronate, calcitonin, raloxifene, selective estrogen modulator (SERM), estrogen therapy, hormone replacement Additional therapeutic agents such as therapy (ET / HRT) and teriparatide) may be used.

One aspect of the present invention provides a method for treating ocular diseases by administering a safe effective amount of a compound of the present invention. An eye disease applicable in the present invention may be associated with a breakdown of the inner blood retinal barrier (iBRB). Representative eye diseases are related to diabetic eye diseases and disorders, including macular edema, diabetic retinopathy and the like. Furthermore, in one embodiment, the present invention relates to a method for treating an ocular disease by administering a compound of the present invention that inhibit Lp-PLA _2. Representative eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, Irvine-Gas syndrome (post-cataract and postoperative), retinitis pigmentosa, ciliary planitis, Shingled chorioretinitis, epiretinal membrane, choroidal tumor, cystic macular edema, parafoveal telangiectasia, tractional maculopathies, vitreous macular traction syndrome, retinal detachment, optic neuroretinitis, idiopathic Examples include macular edema.

  Furthermore, certain embodiments of the invention provide a method for treating diabetic macular edema in a subject. The method includes administering to a subject in need thereof a safe effective amount of a compound of the invention.

  In certain embodiments, the present invention provides a method of treating a subject having or at risk for macular edema. The method includes administering to the subject a safe effective amount of a compound of the invention. In a further embodiment, macular edema is associated with diabetic eye disease, exemplified by diabetic retinopathy. In yet a further embodiment, the macular edema is associated with posterior uveitis.

  In certain embodiments, the present invention provides a method of treating glaucoma or macular degeneration. The method includes administering to the subject a safe effective amount of a compound of the invention.

  In one embodiment, the present invention provides a method of treating a disease associated with a breakdown of the inner blood retinal barrier in a subject in need thereof. The method includes administering to the subject a safe effective amount of a compound of the invention.

  In one embodiment, juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome, Systemic inflammatory diseases such as Lyme disease, Behcet's disease, ankylosing sponsylitis, chronic granulomatosis, and tendon attachment inflammation may be the underlying cause of posterior uveitis affecting the retina, It can cause macular edema. The present invention relates to a method of treating posterior uveitis or these systemic inflammatory diseases by administering a safe effective amount of a compound of the present invention.

Lp-PLA ₂ inhibitors are considered may have beneficial effects against indications associated with M1 / M2 macrophage polarization (macrophage polarization). This idea is based on the following research. A study was conducted by GSK to investigate the relationship between M1 / M2 macrophage polarization and various diseases. 94 human markers described in Martinez FO et al., Which distinguished M1 and M2 phenotypes, were used against the GeneLogic database contracted and used by GSK (Martinez FO et al. (2006) J Immunol 177, 7303 -7311). The connectivity map method described in Lamb J et al. Was used to identify sample fractions in each disease state with expression characteristics consistent with M1-dominant or M2-dominant macrophage populations (Lamb J et al. (2006) Science 313). , 1929-1935) (see PMID 17008526)). This study showed that cirrhosis, skin psoriasis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, and aortic aneurysms have an M1 / M2 imbalance.

Further studies were conducted to investigate the effect of Lp-PLA ₂ inhibitors on the modulation of M1 / M2 imbalance. In this study, immunization with myelin basic protein (MBP) antigen induced the development of experimental autoimmune encephalomyelitis (EAE) in rats and the known Lp-PLA ₂ inhibitor: 5- ( (9-methoxy-4-oxo-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-2-yl) oxy) -2- (3- (trifluoromethyl) phenoxy) benzonitrile (PCT Application No. PCT / CN2011 / 001597). In this prophylactic treatment model, the compound was administered on day 0 (day of immunization) and continued until day 22. The study lasted 25 days. Subsequently, rats were monitored for EAE symptoms. Rats were immunized with MBP to develop EAE and symptoms were monitored daily. Plasma Lp-PLA ₂ activity, OxLDL, and LysoPC concentrations were measured at various time points throughout the course of EAE. This result, plasma Lp-PLA ₂ activity, OxLDL, and LysoPC concentrations that clinical EAE disease in this model is increased with progress is shown, this is, they were contributing to pathogenesis It suggests that. Lp-PLA ₂ inhibitor therapy resulted in a reduction of the clinical disease associated with a decrease in Lp-PLA ₂ activity and LysoPC levels in rat EAE plasma. Thus, inhibition of Lp-PLA ₂ activity in a rat EAE model is beneficial in disease remission.

  In vitro analysis of pro-inflammatory (M1) and anti-inflammatory (M2) markers in control and compound-treated EAE rats. Spleen macrophages were harvested on day 13 after MBP immunization and analyzed for expression of various markers by real-time PCR. CNS infiltrating cells were harvested and macrophages were analyzed for expression of M1 and M2 markers by real-time PCR. Treatment with compounds resulted in a decrease in M1 marker and an increase in M2 marker, potentially suggesting anti-inflammatory and tissue repair potential.

  Accordingly, in certain embodiments, the present invention provides a method for treating diseases associated with macrophage polarization, for example M1 / M2 macrophage polarization. Representative diseases associated with macrophage polarization include, but are not limited to, cirrhosis, skin psoriasis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis And other autoimmune diseases associated with macrophage polarization.

  One aspect of the present invention provides the use of a compound of the present invention for the manufacture of a medicament for performing the methods described herein. Another aspect of the present invention provides a compound of the present invention for use in practicing the therapeutic methods described herein. A further aspect of the invention provides a compound described herein or a pharmaceutically acceptable salt thereof for use in therapy.

F. Compositions The compounds of the present invention may be formulated into a pharmaceutical composition prior to administration to a subject. Accordingly, one aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention and one or more pharmaceutically acceptable excipients. According to another aspect of the invention, a compound of formula (I), formula (IA), formula (IB), formula (IC), or a salt thereof, a solvate thereof, etc. There is provided a process for making a pharmaceutical composition comprising admixing with an acceptable excipient.

  The pharmaceutical composition may be provided as a unit dosage form containing a predetermined amount of the active ingredient per unit dose. Such units may be, for example, 0.1 mg, 0.5 mg, or 1 mg to 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, depending on the condition being treated, the route of administration, and the age, weight, and condition of the subject. 750 mg, or 1 g of a compound of the invention may be contained, or the pharmaceutical composition may be provided as a unit dosage form containing a predetermined amount of the active ingredient per unit dose. In other embodiments, the unit dose composition is one containing a daily dose or sub-dose as described herein of the active ingredient, or an appropriate portion thereof. Furthermore, such pharmaceutical compositions may be made by any method known to those skilled in the art.

  Effective amounts of the compounds of the present invention will vary depending on a number of factors including the intended recipient's age and weight, the exact condition requiring treatment and its severity, the nature of the formulation, and the route of administration. Specifically, it depends on the judgment of the doctor in charge of prescribing medication. However, an effective amount of a compound of the invention for treating anemia is generally in the range of 0.1 to 100 mg / kg of the recipient's body weight per day, and more usually Within the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70 kg adult adult, the actual amount per day is usually 70 to 700 mg, which is a single dose per day or 2, 3, 4, 5 per day. Or multiple sub-doses per day, such as 6 doses. Alternatively, administration may be performed intermittently, such as once every other day, once a week, or once a month. An effective amount, such as a salt or solvate, may be determined in proportion to the effective amount of the compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC) itself. It is envisioned that similar doses are appropriate for the treatment of the other conditions described above.

  The pharmaceutical composition of the present invention may contain one or more compounds of the present invention. In certain embodiments, a pharmaceutical composition may contain more than one compound of the invention. For example, in certain embodiments, a pharmaceutical composition may contain more than one compound of the invention. In addition, the pharmaceutical composition may further comprise one or more additional pharmacologically active compounds, as desired.

  As used herein, “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable substance, composition, or vehicle involved in imparting shape or fastness to a pharmaceutical composition. means. Each of the excipients interacts that, when administered to a subject, will substantially reduce the potency of the compounds of the invention, and will result in a pharmacologically unacceptable pharmaceutical composition. It may be compatible with the other ingredients of the pharmaceutical composition when mixed so that the effect is avoided.

  The compounds of the present invention and one or more pharmaceutically acceptable excipients may be formulated into dosage forms that are compatible with administration to a subject by the desired route of administration. For example, dosage forms include (1) for oral administration (buccal or sublingual) such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets (2) For parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal) such as sterile solutions, suspensions, and powders for reconstitution, (3) Transdermal patches, etc. For skin administration, (4) for rectal administration such as suppositories, (5) for nasal inhalation such as dry powders, aerosols, suspensions and solutions, and (6) creams, ointments, lotions, solutions, pastes, Those adapted for topical administration (including buccal, sublingual or transdermal) such as sprays, foams and gels. Such compositions may be made by any method known in the pharmaceutical arts, for example, a compound of formula (I), formula (IA), formula (IB), or formula (IC), By associating with one or more carriers or excipients.

  Pharmaceutical compositions adapted for oral administration include discrete units such as capsules or tablets, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, ingestible foams or whipped, or oil-in-water liquid emulsions Alternatively, it may be provided as a water-in-oil liquid emulsion.

  Suitable pharmaceutically acceptable excipients can vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the particular function they can act on in the composition. For example, a particular pharmaceutically acceptable excipient may be selected for its ability to facilitate the creation of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the creation of stable dosage forms. Facilitates transport or delivery of one or more compounds of the invention from one organ or body part to another organ or body part after administration of a particular pharmaceutically acceptable excipient to a subject You may choose for that ability. Certain pharmaceutically acceptable excipients may be selected for their ability to improve patient compliance.

  Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents. , Wetting agent, solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, flavor masking agent, coloring agent, anti-caking agent, humectants, chelating agent, plasticizer, thickener, oxidation Inhibitors, preservatives, stabilizers, surfactants, and buffers. One skilled in the art will recognize that a particular pharmaceutically acceptable excipient can perform more than one function, as well as the amount of that excipient present in the formulation and other It is understood that the function as another option may be exhibited depending on the type of the component.

A person skilled in the art has the knowledge and skill in the art to be able to select an appropriate amount of an appropriate pharmaceutically acceptable excipient for use in the present invention. In addition, numerous sources of information are available by those of skill in the art that describe pharmaceutically acceptable excipients and that may be useful in the selection of suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the present invention are made using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

  In one aspect, the invention relates to a solid oral dosage form, such as a tablet or capsule, comprising a safe effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg, corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (eg, microcrystalline cellulose), calcium sulfate As well as dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (eg, corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, tragacanth gum, guar gum, povidone, and cellulose and its derivatives (eg, microcrystalline cellulose). Is mentioned. The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethylcellulose. The oral solid dosage form may further contain a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

  In certain embodiments, the invention provides 0.01 to 1000 mg of one or more compounds described herein or a pharmaceutically acceptable salt thereof, and 0.01 to 5 g of one or more pharmaceutically acceptable salts. It relates to a pharmaceutical composition comprising an acceptable excipient.

  In another embodiment, the invention relates to a pharmaceutical composition for the treatment of a neurodegenerative disease comprising a compound described herein or a pharmaceutically acceptable salt thereof.

Claims (19)

A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:

(Where
R is H or C ₁ -C ₆ alkyl;
R ′ is H, halo, or C ₁ -C ₆ alkyl;
X is —O—, —NH—, —N (C ₁ -C ₆ alkyl)-, —S—, or —CH ₂ —;
n is 0, 1, 2, or 3, and when X is —CH ₂ —, n is 1 or 2.
Ar is phenyl or heteroaryl, any of which is unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C ₆ alkyl, C Substituted with one or more groups selected from the group consisting of ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Y is absent or —O—Ar ′, —NH—Ar ′, —N (C ₁ -C ₆ alkyl) -Ar ′, or — (CH ₂ ) —Ar ′;
Where Ar ′ is phenyl or heteroaryl, any of which are unsubstituted or CN, halo, OH, —NH ₂ , —NHR ₁ , —NR ₁ R ₂ , C ₁ -C Substituted with one or more groups selected from the group consisting of ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl, and
Each occurrence of R ₁ and R ₂ is independently C ₁ -C ₆ alkyl). The compound of claim 1, wherein R is CH ₃ .   The compound according to claim 1 or 2, wherein R 'is H.   The compound according to any one of claims 1 to 3, wherein X is -O-.   The compound according to any one of claims 1 to 4, wherein n is 1 or 2. Ar is unsubstituted phenyl or phenyl substituted with one or more groups selected from the group consisting of CN, F, CF ₃ , Cl, OMe, and CH ₃ , or Ar is none 6. A compound according to any one of claims 1 to 5, which is pyridinyl or thiophenyl which is substituted or substituted with one or more F. Y is absent or Y is —O—Ar ′, where Ar ′ is selected from the group consisting of unsubstituted phenyl or CF ₃ , F, Cl, CN, and CH ₃ Phenyl substituted with one or more groups, or Ar ′ is either unsubstituted or substituted with one or more groups selected from the group consisting of CF ₃ and CH ₃ 7. A compound according to any one of claims 1 to 6 which is a certain pyridinyl or pyrimidinyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of the following formula (IB):

(Wherein Re, Rf, and Rg are independently selected from the group consisting of hydrogen, CN, halo, and CF ₃ ). 8-((3,5-difluoro-4-((6- (trifluoromethyl) pyridin-3-yl) oxy) benzyl) oxy) -1-methyl-3,4-dihydro-1H-pyrimido [1, 6-a] pyrimidin-6 (2H) -one or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has a structure of the following formula (IC):

(Where
R is CH ₃ or iso-propyl;
n is 1 or 2,
Ri is selected from the group consisting of F, Cl, and H;
Rj is selected from the group consisting of H, F, Cl, CF ₃ , CN, and OCH ₃ ;
Rh is selected from the group consisting of H, F, Cl, CN, and CF ₃ , and
Rk is selected from the group consisting of H, F, and CN). The compound according to claim 10 having the following structure or a pharmaceutically acceptable salt thereof:

  A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.   A method for the treatment of a neurodegenerative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 is used in a subject in need thereof. Administering an effective amount to the subject.   14. A method according to claim 13, wherein the neurodegenerative disease is Alzheimer's disease.   12. A method of treating atherosclerosis, the compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable thereof, for performing in a subject in need thereof Administering an effective amount of salt to a subject.   The method according to any one of claims 13 to 15, wherein the subject is a human.   Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease according to any one of claims 13 to 15.   A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in a treatment according to any one of claims 13 to 15.   12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in therapy.